(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization
International Bureau
' llllllllllllllllllllllllllllllllllllllllllllllllll
(43) International Publication Date
3 March 2005 (03.03.2005)
PCT
(10) International Publication Number
WO 2005/018555 A2
(51) International Patent Classification 7 :
(22) International Filing Date: 12 August 2004 (12.08 2004)
(25) Filing Language:
(26) Publication Language:
(30) Priority Data:
10/640,904
60/515,604
60/544,561
English
English
14 August 2003 (14.08.2003)
30 October 2003 (30.10.2003)
13 February 2004 (13.02.2004)
US
(71) Applicant (for all designated States except US): 3M
j INNOVATIVE PROPERTIES COMPANY [US/US];
j 3M Center, Post Office Box 33427, Saint Paul, Minnesota
i 55133-3427 (US).
j (72) Inventor; and
I (75) Inventor/Applicant (for US only): WIGHTMAN, Paul
j D., [US/US] ; Post Office Box 33427, Saint Paul, Minnesota
I 55133-3427 (US).
j (74) Agents: ERSFELD, Dean A., etal.; Office of Intellectual
i Property Counsel, Post Office Box 33427, Saint Paul, Min-
j nesota 55133-3427 (US).
! (81) Designated States (unless otherwise indicated, for every
\ kind of national protection available): AE, AG, AL, AM,
i AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
! CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FT,
i GB, GD, GE, GH, GM, HR, HU, ID, 1L, IN, IS, JP, KE,
KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
MG, MK, MN, MW, MX, MZ, NA, NT, NO, NZ, OM, PG,
PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
ZW.
(84) Designated States (unless otherwise indicated, for every
kind af regional protection available): ARIPO (BW, (ill,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, ML, MR, NE, SN, TD, TG).
Declarations under Rule 4.17:
— as to applicant's entitlement to apply for and be granted
a patent ( Rule 4. 17(H)) for the following designations AE,
AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ,
CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE,
EG, ES, El. GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS,
JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM,
PG. PH, PL. PT. RO. RU. SC, SD, SE, SG, SK, SL, SY, TJ,
TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, YU, ZA, ZM,
ZW, AR1PO patent (BW, GH, GM, KE, LS, MW, MZ, NA,
SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent. (AM, AZ,
BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR, HU, IE,
IT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR), OAPI patent
(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE,
SN, TD. TG)
— as to the applicant's entitlement to claim the priority of the
eartier application (Rule 4.17( Hi)) for all designations
[ Continued o\
U page]
\ (54) Title: LIPID-MODIFIED IMMUNE RESPONSE MODIFIERS
= 10 4
O 10 1
O
10 l
.21
H-2K b /SIINFEKL tetramer
(57) Abstract: Lipid-modified immune response
modifier compounds, pharmaceutical compositions
containing the compounds and methods of use of these
compounds as immunomodulators, for inducing or
inhibiting cytokine biosynthesis in animals and in the
treatment of diseases including viral and neoplastic
diseases, are disclosed.
WO 2005/018555 A2 ill! I IIIIIIIIM
— as to the applicant's entitlement to claim the priority of the
earlier application (Rule 4. 17 (Hi)) for all designations
— as to the applicant's entitlement to claim the priority of the
earlier application (Rule 4.17(iii))for all designations
Published:
— without international search report audio he republished
upon receipt of that report
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at die begin-
ning of each regular issue of the PCT Gazette.
WO 2005/018555
PCT7US2004/026157
LIPID-MODIFIED IMMUNE RESPONSE MODIFIERS
5
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Patent Application Serial No.
10/640904, filed on August 14, 2003, and to U.S. Provisional Patent Application
Serial Nos. 60/515604, filed on October 30, 2003, and 60/544561, filed on
February 13, 2004, each of which is incorporated herein by reference in their
entirety.
BACKGROUND
In the 1950's the li7-imidazo[4,5-c]quinoline ring system was developed,
and l-(6-methoxy-8-quinolinyl)-2-methyl-l//-imidazo[4,5-c]quinoline was
synthesized for possible use as an antimalarial agent. Subsequently, syntheses of
various substituted li/-imidazo[4,5-e] quinolines were reported. For example,
l-[2-(4-piperidyl)ethyl]-li7-imidazo[4,5-c]quinoline was synthesized as a
possible anticonvulsant and cardiovascular agent. Also, several 2-
oxoimidazo[4,5-c]quinolines have been reported.
Certain l//-imidazo[4,5-c]quinoHn-4-amines and 1- and 2-substituted
derivatives thereof were later found to be useful as antiviral agents,
bronchodilators and immunomodulators. Subsequently, certain substituted IH-
imidazo[4,5-c] pyridin-4-amine, quinolin-4-amine, tetrahydroquinolin-4-amine,
naphthyridin-4-amine, and tetrahydronaphthyridin-4-amine compounds as well
as certain analogous thiazolo and oxazolo compounds were synthesized and
found to be useful as immune response modifiers (IRMs), rendering them useful
in the treatment of a variety of disorders.
There continues to be interest in and a need for compounds that have the
ability to modulate the immune response, by induction of cytokine biosynthesis
or other mechanisms.
WO 2005/018555
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SUMMARY
A new class of compounds useful for modulating cytokine biosynthesis
has now been found, hi one aspect, the present invention provides an IRM
compound covalently bound to an R] group wherein Ri is as defined below; and
5 pharmaceutically acceptable salts thereof, hi one embodiment, the present
invention provides such compounds, which are of Formula I:
I
wherein R A , Rb, Ri, and R" are as defined below; and pharmaceutically
10 acceptable salts thereof.
Examples of such compounds include those of the following Formulas n,
HI, IV, V, VI, and VII:
WO 2005/018555
PCT7US2004/026157
vn
10
wherein R 5 R A , Rb, Ri, R2, and n are as defined below; and pharmaceutically
acceptable salts thereof.
ERM compounds covalently bound to an Ri group including the
compounds of Formula I are useful as immune response modifiers (IRMs) due to
1 5 their ability to induce or inhibit cytokine biosynthesis (e.g., induce or inhibit the
biosynthesis or production of one or more cytokines) and otherwise modulate the
immune response when administered to animals. This makes the compounds
useful in the treatment of a variety of conditions such as viral diseases,
neoplastic diseases, and autoimmune diseases that are responsive to such
20 changes in the immune response.
hi another aspect, the present invention provides pharmaceutical
compositions containing the immune response modifier compounds, and
methods of inducing or inhibiting cytokine biosynthesis in an animal, treating a
viral disease in an animal, and treating a neoplastic disease in an animal, by
WO 2005/018555
PCT7US2004/026157
administering an effective amount of one or more compounds of Formula I
and/or pharmaceutically acceptable salts thereof to the animal.
As used herein, "a," "an," "the," "at least one," and "one or more" are
used interchangeably.
5 The terms "comprising" and variations thereof do not have a limiting
meaning where these terms appear in the description and claims.
The above summary of the present invention is not intended to describe
each disclosed embodiment or every implementation of the present invention.
The description that follows more particularly exemplifies illustrative
10 embodiments. Guidance is also provided herein through lists of examples,
which can be used in various combinations. In each instance, the recited list
serves only as a representative group and should not be interpreted as an
exclusive list.
1 5 BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows expansion of antigen-specific CD8 + T cells after
immunization with ovalbumin, as described in Example 5.
Figure 2 shows expansion of antigen-specific CD8 + T cells in one subject
after immunization with a colloidal suspension of IRM and ovalbumin, as
20 described in Example 5.
Figure 3 shows expansion of antigen-specific CD8 + T cells in a second
subject after immunization with a colloidal suspension of IRM and ovalbumin,
as described in Example 5.
25 DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
OF THE INVENTION
The present invention provides a new class of compounds in which an
IRM compound is covalently bound to an Ri group wherein Ri is as defined
below; and pharmaceutically acceptable salts thereof. More specifically, the
30 present invention provides compounds of the following Formulas I through VII:
WO 2005/018555
PCT7US2004/026157
IV
15
WO 2005/018555
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NH,
VI
NH 2
r >-r 2
"N
(R)rT
Ri
5
vn
wherein R, R A , R B , Ri, R2, R", and n are as defined below; and pharmaceutically
acceptable salts thereof.
In one aspect, the present invention provides an IRM compound
10 covalently bound to an Ri group wherein Ri has the formula alkylene-L-Ri-i,
alkenylene-L-R M , or alkynylene-L-Ri-i, wherein:
the alkylene, alkenylene, and alkynylene groups are optionally interrupted
with one or more -O- groups (preferably, interrupted with one -O- group);
L is a bond or a functional linking group; and
15 R1-1 is a linear or branched aliphatic group having at least 1 1 carbon
atoms (preferably, at least 12 carbon atoms), optionally including one or more
unsaturated carbon-carbon bonds; or a pharmaceutically acceptable salt thereof;
with the proviso that for a compound of Formula I:
optionally including one or more unsaturated carbon-carbon bonds; and with the
25 further proviso that for a compound of Formula I when L is -NH-C(O)- and R A
NH,
20
I
when L is -NH-S(0) 2 - and R A and R B join to form an unsubstituted benzene ring,
Ri_! is a linear or branched aliphatic group having greater than 16 carbon atoms,
WO 2005/018555
PCT7US2004/026157
and R B join to form an unsubstituted pyridine ring, Ri-i is a linear or branched
aliphatic group having greater than 1 1 carbon atoms, optionally including one or
more unsaturated carbon-carbon bonds.
In one embodiment, the present invention provides compounds of the
following Formula I:
NH 2
>
N
I
R A Ri
I
wherein:
R! has the formula alkylene-L-Ri-i, alkenylene-L-Ri_i, or
alkynylene-L-Ri.i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups (preferably,
with one -O- group);
L is a bond or a functional linking group; and
Ri-i is a linear or branched aliphatic group having at least
1 1 carbon atoms (preferably, at least 1 2 carbon atoms), optionally
including one or more unsaturated carbon-carbon bonds;
R" is hydrogen or a non-interfering substituent;
R A and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
alkenyl,
alkoxy,
allcylthio, and
-N(R 3 ) 2 ;
or when taken together, R A and R B form a fused aryl ring or heteroaryl
ring containing one heteroatom or a fused 5- to 7-membered saturated ring,
optionally containing one heteroatom, wherein the heteroatom is selected from
the group consisting of N and S, and wherein the aryl, heteroaryl, or 5- to 7-
WO 2005/018555
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membered saturated ring is unsubstituted or substituted by one or more non-
interfering substituents; and
R 3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-S(0) 2 - and R A and R B join to form an
5 unsubstituted benzene ring, Ri-i is a linear or branched aliphatic group having
greater than 16 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds; and with the further proviso that when L is -NH-C(O)- and
R A and R B join to form an unsubstituted pyridine ring, Ri-i is a linear or
branched aliphatic group having greater than 1 1 carbon atoms, optionally
10 including one or more unsaturated carbon-carbon bonds;
or apharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides compounds of the
following Formula II:
15
n
wherein:
Ri has the formula alkylene-L-Ri-i, alkenylene-L-Ri-i, or
alkynylene-L-Ri-i, wherein:
20
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups (preferably,
with one -O- group);
25
L is a bond or a functional linking group selected from the
group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
Ri_i is a linear or branched aliphatic group having at least
11 carbon atoms (preferably, at least 12 carbon atoms), optionally
including one or more unsaturated carbon-carbon bonds;
30
R 2 is selected from the group consisting of:
hydrogen;
-8-
WO 2005/018555 PCT7US2004/026157
alkyl;
alkenyl;
aryl;
heteroaryl;
5 heterocyclyl;
alkylene-Y-alkyl;
alkylene-Y- alkenyl;
alkylene-Y-aryl; and
alkyl or alkenyl substituted by one or more substituents selected
0 from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
-C(O)-Ci-i 0 alkyl;
5 -C(O)-O-Ci.i 0 alkyl;
-N 3 ;
aryl;
heteroaryl;
heterocyclyl;
10 -C(0)-aryl; and
-C(0)-heteroaryl;
wherein: Y is -O- or -S(O) 0 -2-; and each R4 is
independently selected from the group consisting of hydrogen,
Ci-ioalkyl, and C 2 -ioalkenyl;
15 Ra and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
alkenyl,
10 alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
-9-
WO 2005/018555
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or when taken together, R A and R B form a fused aryl ring or heteroaryl
ring containing one heteroatom wherein the aryl or heteroaryl ring is
unsubstituted or substituted by one or more R groups; or when taken together, R A
and R B form a fused 5- to 7-membered saturated ring, optionally containing one
5 heteroatom selected from the group consisting of N and S, and unsubstituted or
substituted by one or more R groups; wherein R is selected from the group
consisting of
halogen,
hydroxy,
10 alkyl,
alkenyl,
halo alkyl,
alkoxy,
alkylthio, and
15 -N(R 3 ) 2 .
and
R 3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-S(0 2 )- and R A and R B join to form an
unsubstituted benzene ring, Ri_i is a linear or branched aliphatic group having at
20 least 16 carbon atoms, optionally including one or more unsaturated carbon-
carbon bonds; and with the further proviso that when L is -NH-C(O)- and R A and
R B join to form an unsubstituted pyridine ring, R M is a linear or branched
aliphatic group having greater than 1 1 carbon atoms, optionally including one or
more unsaturated carbon-carbon bonds;
25 or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides compounds of the
following Formula H:
30
wherein:
n
-10-
WO 2005/018555
PCT7US2004/026157
Ri has the formula alkylene-L-Ri-i, alkenylene-L-Ri„i, or
alkynylene-L-Ri-i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups (preferably,
with one -O- group);
Lis a bond or a functional linking group selected from the
group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
R!-! is a linear or branched aliphatic group having at least
11 carbon atoms (preferably, at least 12 carbon atoms), optionally
including one or more unsaturated carbon-carbon bonds;
R 2 is selected from the group consisting of:
hydrogen;
alkyl;
alkenyl;
aryl;
heteroaryl;
heterocyclyl;
alkylene-Y-alkyl;
alkylene- Y- alkenyl;
alkylene- Y-aryl; and
alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
-C(O)-Ci-i 0 alkyl;
-C(O)-O-Ci- 10 alkyl;
-N 3 ;
aryl;
heteroaryl;
heterocyclyl;
-11-
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-C(0)-aryl; and
-C(0)-heteroaryl;
wherein: Y is -O- or -S(O) 0 -2-; and each R4 is
independently selected from the group consisting of hydrogen,
Ci.ioalkyl, and C 2 -ioalkenyl;
R A and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
alkenyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ; and
R 3 is selected from the group consisting of hydrogen and alkyl;
or apharmaceutically acceptable salt thereof.
hi another embodiment, the present invention provides compounds of the
following Formula HI:
NH 2
m
wherein:
Ri has the formula alkylene-L-Ri-i, alkenylene-L-Ri_i, or
alkynylene-L-Ri-i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups (preferably,
with one -O- group);
L is a bond or a functional linking group selected from the
group consisting of -NH-S(0) r , -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
-12-
WO 2005/018555
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Ri-i is a linear or branched aliphatic group having at least
11 carbon atoms (preferably, at least 12 carbon atoms), optionally
including one or more unsaturated carbon-carbon bonds;
R is selected from the group consisting of
5 halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
10 alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
n is 0 to 4;
R 2 is selected from the group consisting of:
15 hydrogen;
alkyl;
alkenyl;
aryl;
heteroaryl;
20 heterocyclyl;
alkylene-Y-alkyl;
alkylene- Y- alkenyl;
alkylene-Y-aryl; and
alkyl or alkenyl substituted by one or more substituents selected
25 from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
-C(O)-Ci-i 0 alkyl;
30 -C(O)-O-Ci-i 0 alkyl;
-N 3 ;
aryl;
heteroaryl;
WO 2005/018555 PCT7US2004/026157
heterocyclyl;
-C(0)-aryl; and
-C(0)-heteroaryl;
Yis-O-or-S(O) 0 -2-;
5 each R4 is independently selected from the group consisting of hydrogen,
Ci-ioalkyl, and C 2 -ioalkenyl; and
R 3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-S(0 2 )-, and n is 0, R1-1 is a linear or
branched aliphatic group having at least 16 carbon atoms, optionally including
10 one or more unsaturated carbon-carbon bonds;
or a pharmaceutically acceptable salt thereof.
In other embodiments, the present invention provides compounds of the
following Formulas IV, V, VI, and VII:
VI vn
wherein:
20 Ri has the formula alkylene-L-RM, alkenylene-L-R M , or
alkynylene-L-Ri.i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups (preferably,
with one -O- group);
25 L is a bond or a functional linking group selected from the
group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-14-
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-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
Ri-i is a linear or branched aliphatic group having at least
1 1 carbon atoms (preferably, at least 12 carbon atoms), optionally
including one or more unsaturated carbon-carbon bonds;
5 R is selected from the group consisting of
halogen,
hydroxy,
alkyl,
alkenyl.,
10 haloalkyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
n is 0 or 1;
15 R 2 is selected from the group consisting of:
hydrogen;
alkyl;
alkenyl;
aryl;
20 heteroaryl;
heterocyclyl;
alkylene-Y-alkyl;
alkylene-Y- alkenyl;
alkylene-Y-aryl; and
25 alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
30 -C(O)-C M0 alkyl;
-C(O)-O-Ci_i 0 alkyl;
-N 3 ;
aryl;
WO 2005/018555
PCT7US2004/026157
heteroaryl;
heterocyclyl;
-C(0)-aryl; and
-C(0)-heteroaryl;
5 Yis-O~or-S(O) 0 - 2 -;
each R4 is independently selected from the group consisting of hydrogen,
Ci.ioalkyl, and C 2 -ioalkenyl; and
R3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-C(O)-, and n is 0, R^t is a linear or
10 branched aliphatic group having at least 12 carbon atoms, optionally including
one or more unsaturated carbon-carbon bonds;
or a pharmaceutically acceptable salt thereof
In the context of the present invention, the term "aliphatic" group means
a saturated or unsaturated linear or branched hydrocarbon group. This term is
15 used to encompass alkyl, alkenyl, and alkynyl groups, for example.
As used herein, the terms "alkyl," "alkenyl," "alkynyl" and the prefix
"alk-" are inclusive of both straight chain and branched chain groups and of
cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these
groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2
20 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms.
In some embodiments, these groups have a total of up to 10 carbon atoms, up to
8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups
can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon
atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl,
25 cyclop entyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl,
norbornyl, and norbornenyl.
Unless otherwise specified, "alkylene," "alkenylene," and "alkynylene"
are the divalent forms of the "alkyl," "alkenyl," and "alkynyl" groups defined
above. Likewise, "alkylenyl," "alkenylenyl," and "alkynylenyl" are the divalent
30 forms of the "alkyl," "alkenyl," and "alkynyl" groups defined above. For
example, an arylalkylenyl group comprises an alkylene moiety to which an aryl
group is attached.
-16-
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The term "haloalkyl" is inclusive of groups that are substituted by one or
more halogen atoms, including perfluorinated groups. This is also true of other
groups that include the prefix "halo-". Examples of suitable haloalkyl groups are
chloromethyl, trifluoromethyl, and the like.
5 The term "aryl" as used herein includes carbocyclic aromatic rings or ring
systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl
and indenyl.
The term "heteroaryl" includes aromatic rings or ring systems that contain
at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include
10 furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl,
pyrrofyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl,
benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl,
quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl,
quinazolinyl, pyrazinyl, 1-oxidopyridyl, and so on.
15 The term "heterocyclyl" includes non-aromatic rings or ring systems that
contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully
saturated and partially unsaturated derivatives of the above mentioned heteroaryl
groups. Exemplary heterocyclic groups include pyrrolidinyl, tehahydrofuranyl,
morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl,
20 imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl,
homopiperidinyl, and the like.
The terms "arylene," "heteroarylene," and "heterocyclylene" are the
divalent forms of the "aryl," "heteroaryl," and "heterocyclyl" groups defined
above. Likewise, "arylenyl," "heteroarylenyl," and "heterocyclylenyl" are the
25 divalent forms of the "aryl," "heteroaryl," and "heterocyclyl" groups defined
above. For example, an alkylarylenyl group comprises an arylene moiety to
which an alkyl group is attached.
When a group (or substituent or variable) is present more than once in
any Formula described herein, each group (or substituent or variable) is
30 independently selected, whether explicitly stated or not. For example, for the
formula -N(R 3 ) 2 each R 3 group is independently selected, hi another example,
when more than one R group is present and each R group contains one or more
-17-
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-N(R 3 ) 2 groups, then each R group is independently selected, and each R 3 group
is independently selected.
The invention is inclusive of the compounds described herein, and salts
thereof, in any of their pharmaceutically acceptable forms, including isomers
5 (e.g., diastereomers and enantiomers), solvates, polymorphs, and the like. In
particular, if a compound is optically active, the invention specifically includes
each of the compound's enantiomers as well as racemic mixtures of the
enantiomers.
In some embodiments, compounds of Formulas I- VII induce the
1 0 biosynthesis of one or more cytokines.
For any of the compounds presented herein, each one of the following
variables (e.g., R, R", Ri, R2, Ra, Rb, n, L, and so on) in any of its embodiments
can be combined with any one or more of the other variables in any of their
embodiments as would be understood by one of skill in the art. Each of the
15 resulting combinations of variables is an embodiment of the present invention.
For certain embodiments, R" is hydrogen or a non-interfering substituent.
Herein, "non-interfering" means that the ability of the compound or salt to
modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not
destroyed by the non-interfering substitutent. Illustrative non-interfering R"
20 groups include those described herein for R 2 . Preferred embodiments of R" and
R 2 are listed below.
The present invention provides an IRM compound covalently bound to
an Ri group. Herein, Ri has the formula alkylene-L-Ri-i, alkenylene-L-Ri-i, or
alkynylene-L-Ri-!, wherein the alkylene, alkenylene, and alkynylene groups are
25 optionally interrupted with one or more -O- groups; L is a bond or a functional
linking group; and R1-1 is a linear or branched aliphatic group having at least 1 1
carbon atoms, optionally including one or more unsaturated carbon-carbon
bonds. In some embodiments, the IRM compound is not imiquimod.
In some embodiments of Formulas I- VII, the alkylene, alkenylene, and
30 alkynylene groups within Ri are linear or branched. In certain embodiments the
alkylene, alkenylene, and alkynylene groups within Ri are linear. In some
embodiments the alkylene, alkenylene, and alkynylene groups are interrupted
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with one or more -O- groups. In some embodiments, the alkylene, alkenylene,
and alkynylene groups are interrupted with one -O- group.
Herein, the Ri is also referred to as Q-L-R1-1 wherein Q is an alkylene,
alkenylene, or alkynylene optionally interrupted with one or more -O- groups, hi
5 some embodiments, Q is an alkylene optionally interrupted with one oxygen
atom (i.e., -O- group). In some embodiments, Ri has the formula
alkylene-L-Ri-i (i.e., Q-L-R1-1) and the alkylene (Q) is optionally interrupted
with one oxygen atom. In some embodiments, Ri has the formula
Ci_5alkylene-L-Ri_i and the d-salkylene is optionally interrupted with one -O-
10 group. Alternatively, stated Q is preferably a Ci- 5 alkylene optionally interrupted
with one -O- group. Examples of preferred Q groups include -(CH 2 ) 2 -, -(CH 2 ) 3 -,
-(CH 2 ) 4 -, -(CH 2 ) 5 -, and -(CH 2 ) 2 -0-(CH 2 ) 2 -.
In some embodiments, L is a bond or a functional linking group selected
from the group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
1 5 -NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -, -NH-C(0)-0, -O-, -S-, and
-S(0) 2 -.
In some embodiments, L is a bond or a functional linking group selected
from the group consisting of -NH-C(O)-, -NH-S(0) 2 -, and -NH-C(0)-N(R 3 )-.
In some embodiments, when L is -NH-S(0)2- and R A and R B join to form
20 an unsubstituted benzene ring, Rm is a linear or branched aliphatic group having
greater than 16 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds, hi some embodiments, when L is -NH-S(0 2 )- ; and n is 0,
Rm is a linear or branched aliphatic group having at least 16 carbon atoms,
optionally including one or more unsaturated carbon-carbon bonds.
25 In some embodiments, when L is -NH-C(O)- and R A and R B join to form
an unsubstituted pyridine ring, Ri-i is a linear or branched aliphatic group having
greater than 1 1 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds. In some embodiments, when L is -NH-C(O)-, and n is 0,
Ri_i is a linear or branched aliphatic group having at least 12 carbon atoms,
30 optionally including one or more unsaturated carbon-carbon bonds.
In some embodiments, R t -i is a linear or branched aliphatic group having
at least 11 carbon atoms (preferably, at least 12 carbon atoms), optionally
including one or more unsaturated carbon-carbon bonds. In some embodiments,
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Ri.i is a linear or branched aliphatic group having 11-20 carbon atoms
(preferably, 12-20 carbon atoms), optionally including one or more unsaturated
carbon-carbon bonds. In some embodiments, Rm is a linear (i.e., straight chain)
alkyl group having 1 1-20 carbon atoms (preferably, 12-20 carbon atoms).
5 Such Rm substituents are desirable because they provide lipid-like
characteristics to compounds of the present invention. This is advantageous
because these lipid moieties can aid in the sequestering of ERM's at the site of
application. That is, the lipid moiety can assist in preventing the rapid diffusion
of an IRM away from the site of administration. This sequestering can result in
1 0 enhanced adjuvancy of an IRM, which could be manifest by enhanced
recruitment and activation of antigen-presenting cells at a desired site.
Furthermore, this sequestering can result in less systemic distribution of an IRM,
and the ability to use lesser amounts of IRM's.
hi some embodiments, R A and R B are each independently selected from
15 the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and
-N(R 3 ) 2 .
In some embodiments, when taken together, Ra and R B form a fused aryl
ring or heteroaryl ring containing one heteroatom or a fused 5- to 7-membered
saturated ring, optionally containing one heteroatom, wherein the heteroatom is
20 selected from the group consisting of N and S, and wherein the aryl, heteroaryl,
or 5- to 7-membered saturated ring is unsubstituted or substituted by one or more
non-interfering substituents. Preferably, the substituents are selected from the
group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy,
alkylthio, and -N(R 3 ) 2 -
25 In some embodiments, when taken together, R A and R B form a fused aryl
ring or heteroaryl ring containing one heteroatom selected from the group
consisting of N and S wherein the aryl or heteroaryl ring is unsubstituted or
substituted by one or more R groups; or when taken together, R A and Rb form a
fused 5- to 7-membered saturated ring, optionally containing one heteroatom
30 selected from the group consisting of N and S, and unsubstituted or substituted
by one or more R groups.
In some embodiments, when taken together, R A and R B form a fused 5- to
7-membered saturated ring, optionally containing one heteroatom selected from
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the group consisting of N and S, and unsubstituted or substituted by one or more
substituents selected from the group consisting of: halogen, hydroxy, alkyl,
alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 3 ) 2 -
hi some embodiments, R A and R B form a fused aryl or heteroaryl ring.
5 In some embodiments, R A and R B form a fused 5- to 7-membered
saturated ring.
In some embodiments, R A and R B form a fused benzene ring which is
unsubstituted.
In some embodiments, R A and R B form a fused pyridine ring which is
10 unsubstituted.
hi some embodiments, R is selected from the group consisting of:
halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 3 ) 2 .
In some embodiments, R" and R 2 are selected from the group consisting of:
hydrogen; alkyl; alkenyl; aryl; heteroaryl; heterocyclyl; alkylene-Y-alkyl;
15 alkylene-Y- alkenyl; alkylene-Y-aryl; andalkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: -OH; halogen;
-N(R4> 2 ; -C(O)-C 1 . 10 alkyl; -C(O)-O-C M0 alkyl; -N 3 ; aryl; heteroaryl;
heterocyclyl; -C(0)-aryl; and -C(0)-heteroaryl. Preferably, in such
embodiments, Y is -O- or -S(O) 0 - 2 -, and each R4 is independently selected from
20 the group consisting of hydrogen, Ci-i 0 alkyl, and C 2 -i 0 alkenyl.
In some embodiments, R" and R 2 are selected from the group consisting
of hydrogen, alkyl, and alkylene-O-alkyl.
In some embodiments, each R3 is independently selected from the group
consisting of hydrogen and alkyl.
25 In some embodiments, each R4 is independently selected from the group
consisting of hydrogen, Ci-ioalkyl, and C 2 -ioalkenyl.
In some embodiments, Y is -O- or -S(O) 0 - 2 --
In some embodiments, n is 0 to 4. In some embodiments, n is 0 or 1 . In
some embodiments, n is 0.
30
Preparation of Compounds
Compounds of the invention can be prepared using synthetic methods
that are known to be useful in the preparation of imidazoquinolines,
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tefrahydroimidazoquinolines, imidazopyridines, imidazonaphthyridines, and
tetrahydroimidazonaphthyridines .
For example, compounds of the invention where L is -NH-C(O)- can be
prepared from conventional fatty acids such as stearic acid, palmitic acid, and
5 linoleic acid using the synthetic methods described in U.S. Patent Nos.
6,451,810; 6,545,016; 6,194,425; 6,660,747; and 6,664,265 andPCT
Publication WO 03/103584.
Compounds of the invention where L is -NH-S(0)2- can be prepared
from sulfonyl chlorides of the formula Ri-iS(0) 2 Cl using the synthetic methods
10 described in U.S. Patent Nos 6,331,539; 6,525,064; 6,194,425; 6,677,347;
6,677,349; and 6,683,088 and PCT Publication WO 03/103584.
Compounds of the invention where L is -NH-C(0)-N(R 3 )- or
-NH-C(S)-N(R 3 )- can be prepared from isocyanates or thioisocyantes of the
formulas Ri_iC=N=0 and RmC=N=S respectively using the synthetic methods
15 described in U.S. Patent Nos. 6,541,485; 6,573,273; 6,656,938; 6,660,735; and
6,545,017 and PCT Publication WO 03/103584.
Compounds of the invention where L is a bond can be prepared from
amines of formula R1.1NH2 using the synthetic methods described in U.S. Patent
Nos. 4,689,338; 4,929,624; 5,268,376; 5,389,640; 5,352,784; and 5,446,153.
20 Compounds of the invention where L is -S- or -S(0) 2 - can be prepared
from mercaptans of formula Ri_]SH using the synthetic methods described in
U.S. Patent Nos. 6,664,264 and 6,667,312.
Pharmaceutical Compositions and Biological Activity
25 Pharmaceutical compositions of the invention contain a therapeutically
effective amount of a compound of the invention as described above in
combination with a pharmaceutically acceptable carrier.
The term "a therapeutically effective amount" or "effective amount"
means an amount of the compound sufficient to induce a therapeutic or
30 prophylactic effect, such as cytokine induction, cytokine inhibition,
immunomodulation, antitumor activity, and/or antiviral activity. Although the
exact amount of active compound used in a pharmaceutical composition of the
invention will vary according to factors known to those of skill in the art, such as
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the physical and chemical nature of the compound, the nature of the carrier, and
the intended dosing regimen, it is anticipated that the compositions of the
invention will contain sufficient active ingredient to provide a dose of about 100
nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg),
5 preferably about 10 micrograms per kilogram (|J.g/kg) to about 5 mg/kg, of the
compound to the subject. A variety of dosage forms may be used, such as
tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments,
aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds of the invention can be administered as the single
10 therapeutic agent in the treatment regimen, or the compounds of the invention
may be administered in combination with one another or with other active
agents, including additional immune response modifiers, antivirals, antibiotics,
antibodies, proteins, peptides, oligonucleotides, etc.
The compounds of the invention have been shown to induce, and certain
1 5 compounds of the invention may inhibit, the production of certain cytokines in
experiments performed according to the tests set forth below. These results
indicate that the compounds are useful as immune response modifiers that can
modulate the immune response in a number of different ways, rendering them
useful in the treatment of a variety of disorders.
20 Cytokines whose production may be induced by the administration of
compounds according to the invention generally include interferon-a (IFN-a)
and/or tumor necrosis factor-a (TNF-a) as well as certain interleukins (IL).
Cytokines whose biosynthesis may be induced by compounds of the invention
include IFN-a, TNF-a, IL-1, IL-6, IL-10 and IL-12, and a variety of other
25 cytokines. Among other effects, these and other cytokines can inhibit virus
production and tumor cell growth, making the compounds useful in the treatment
of viral diseases and neoplastic diseases. Accordingly, the invention provides a
method of inducing cytokine biosynthesis in an animal comprising administering
an effective amount of a compound or composition of the invention to the
30 animal. The animal to which the compound or composition is administered for
induction of cytokine biosynthesis may have a disease as described infra, for
example a viral disease or a neoplastic disease, and administration of the
compound may provide therapeutic treatment. Alternatively, the compound may
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be administered to the animal prior to the animal acquiring the disease so that
administration of the compound may provide a prophylactic treatment.
In addition to the ability to induce the production of cytokines,
compounds of the invention may affect other aspects of the innate immune
5 response. For example, natural killer cell activity may be stimulated, an effect
that may be due to cytokine induction. The compounds may also activate
macrophages, which in turn stimulate secretion of nitric oxide and the production
of additional cytokines. Further, the compounds may cause proliferation and
differentiation of B-lymphocytes.
10 Compounds of the invention can also have an effect on the acquired
immune response. For example, the production of the T helper type 1 (T H 1)
cytokine IFN-y may be induced indirectly and the production of the T helper type
2 (T H 2) cytokines IL-4, IL-5 and EL-13 maybe inhibited upon administration of
the compounds.
1 5 Other cytokines whose production may be inhibited by the administration
of certain compounds according to the invention include tumor necrosis factor-a
(TNF-a). Among other effects, inhibition of TNF-a production can provide
prophylaxis or therapeutic treatment of diseases in animals in which TNF is
mediated, making the compounds useful in the treatment of, for example,
20 autoimmune diseases. Accordingly, the invention provides a method of
inhibiting TNF-a biosynthesis in an animal comprising administering an
effective amount of a compound or composition of the invention to the animal.
The animal to which the compound or composition is administered for inhibition
of TNF-a biosynthesis may have a disease as described infra, for example an
25 autoimmune disease, and administration of the compound may provide
therapeutic treatment. Alternatively, the compound may be administered to the
animal prior to the animal aquiring the disease so that administration of the
compound may provide a prophylactic treatment.
Whether for prophylaxis or therapeutic treatment of a disease, and
30 whether for effecting innate or acquired immunity, the compound or composition
may be administered alone or in combination with one or more active
components as in, for example, a vaccine adjuvant. When administered with
other components, the compound and other component or components may be
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administered separately; together but independently such as in a solution; or
together and associated with one another such as (a) covalently linked or (b) non-
covalently associated, e.g., in a colloidal suspension.
Conditions for which ERMs identified herein may be used as treatments
5 include, but are not limited to:
(a) viral diseases such as, for example, diseases resulting from infection
by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-H, CMV, or VZV), a
poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum
contagiosum), a picomavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus
10 (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus,
measles virus, and respiratory syncytial virus (RSV), a coronavirus (e.g., SARS),
a papovavirus, (e.g., papillomaviruses, such as those that cause genital warts,
common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B virus), a
flavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
15 lentivirus such as HIV);
(b) bacterial diseases, such as, for example, diseases resulting from
infection by bacteria of, for example, the genus Escherichia, Enterobacter,
Salmonella, Staphylococci, Shigella, Listeria, Aerobacter, Helicobacter,
Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma,
20 Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium,
Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia,
Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) other infectious diseases, such as chlamydia, fungal diseases, such as,
for example, candidiasis, aspergillosis, histoplasmonsis, cryptococcal meningitis,
25 or parasitic diseases, such as, for example, malaria, Pneumocystis caxnii
pneomonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome
infection;
(d) neoplastic diseases, such as intraepithelial neoplasias, cervical
dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, aenal
30 cell leukemia, Karposi's sarcoma, melanoma, renal cell carcinoma, leukemias,
such as, for example, myelogeous leukemia, chronic lymphocytic leukemia, and
multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-
cell lymphoma, hairy cell leukemia, and other cancers; and
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(e) T H 2-mediated, atopic, and. autoimmune diseases, such as atopic
dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, systemic
lupus erythematosis, essential thrombocythaemia, multiple sclerosis, Ommen's
syndrome, discoid lupus, alopecia areata, inhibition of keloid formation and
5 other types of scarring, and enhancing wound healing, including chronic wounds.
IRMs identified herein also maybe useful as a vaccine adjuvant for use
in conjunction with any material that raises either humoral and/or cell mediated
immune response, such as, for example, live viral, bacterial, or parasitic
imrnunogens; inactivated viral, tumor-derived, protozoal, organism-derived,
10 fungal, or bacterial immunogens, toxoids, toxins; self-antigens; polysaccharides;
proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant
proteins; and the like, for use in connection with, for example, BCG, cholera,
plague, typhoid, hepatitis A, hepatitis B, and hepatitis C, influenza A and
influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever,
1 5 tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningococcal and
pneumococcal vaccines, adenovirus, HIV, chicken pox, cytomegalovirus,
dengue, feline leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, Japanese
encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow fever,
and Alzheimer's Disease.
20 IRMs may also be particularly helpful in individuals having
compromised immune function. For example, ERM compounds may be used for
treating the opportunistic infections and tumors that occur after suppression of
cell mediated immunity in, for example, transplant patients, cancer patients and
HIV patients.
25 Thus, one or more of the above diseases or types of diseases, for
example, a viral disease or a neoplastic disease may be treated in an animal in
need thereof (having the disease) by administering a therapeutically effective
amount of a compound or salt of Formula I, II, m, IV, V, VI, VII, or a
combination thereof to the animal. An animal may also be vaccinated by
30 administering an effecive amount of a compound or salt of Formula I, II, HI, IV,
V, VI, VII, or a combination thereof to the animal as a vaccine adjuvant.
An amount of a compound effective to induce cytokine biosynthesis is an
amount sufficient to cause one or more cell types, such as monocytes,
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macrophages, dendritic cells and B-cells to produce an amount of one or more
cytokines such as, for example, IFN-a, TNF-a, IL-1, EL-6, IL-10 and IL-12 that is
increased over the background level of such cytokines. The precise amount will
vary according to factors known in the art but is expected to be a dose of about
5 1 00 ng/kg to about 50 mg/kg, preferably about 1 0 ug/kg to about 5 mg/kg. The
invention also provides a method of treating a viral infection in an animal and a
method of treating a neoplastic disease in an animal comprising administering an
effective amount of a compound or composition of the invention to the animal.
An amount effective to treat or inhibit a viral infection is an amount that
10 will cause a reduction in one or more of the manifestations of viral infection,
such as viral lesions, viral load, rate of virus production, and mortality as
compared to untreated control animals. The precise amount that is effective for
such treatment will vary according to factors known in the art but is expected to
be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 jag/kg to
1 5 about 5 mg/kg. An amount of a compound effective to treat a neoplastic
condition is an amount that will cause a reduction in tumor size or in the number
of tumor foci. Again, the precise amount will vary according to factors known
in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 ng/kg to about 5 mg/kg.
20 In certain embodiments, there is provided a method of inducing cytokine
biosynthesis in an animal comprising administering an effective amount of a
compound or salt described herein to the animal. In another embodiment, there
is provided a method of treating a viral disease in an animal comprising
administering a therapeutically effective amount of a compound or salt described
25 herein to the animal. In another embodiment, there is provided a method of
treating a neoplastic disease in an animal comprising administering a
therapeutically effective amount of a compound or salt described herein to the
animal, hi another embodiment, there is provided a method of vaccinating an
animal comprising administering an effecive amount of a compound or salt
30 described herein to the animal as a vaccine adjuvant. In another embodiment,
there is provided a method of vaccinating an animal comprising administering an
effecive amount of N-(2- {2-[4-arriino-2-(2-methoxyethyl)-l J f/-imidazo[4,5-
c]quinolin-l-yl]ethoxy}ethyl)hexadecanamide to the animal as a vaccine
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adjuvant. In another embodiment, there is provided a method of vaccinating an
animal comprising administering an effecive amount of A^(2-{2~[4-amino-2-(2-
methoxyethyl)-li74midazo[4,5-c]quinolin-l-yl]ethoxy}ethyl)octadecanamide to
the animal as a vaccine adjuvant, hi another embodiment, there is provided a
5 method of vaccinating an animal comprising administering an effecive amount
ofiV-(2-{2-[4-amino-2-(2-methoxyethyl)-li^-imidazo[4,5-c]quinolin-l-
yl]ethoxy}ethyl)dodecanamide to the animal as a vaccine adjuvant, hi another
embodiment, there is provided a method of vaccinating an animal comprising
administering an effecive amount of A f -(2-{2-[4-amino-2-(2-methoxyethyl)-liy-
10 imidazo[4,5-c]quinolm-l-yl]ethoxy}ethyl)tetradecanamide to the animal as a
vaccine adjuvant.
Objects and advantages of this invention are further illustrated by the
following examples, but the particular materials and amounts thereof recited in
15 these examples, as well as other conditions and details, should not be construed to
unduly limit this invention.
20
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EXAMPLES
10
15
20
Example 1
Preparation of A^-(2-{2-[4-amino-2-(2-methoxyethyl)-lif-imidazo[4,5-
c] quinolin- 1 -yl] ethoxy } ethyl)hexadecanamide
A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180 mL of
tetrahydrofuran (THF), under N 2 , was cooled to 0°C and treated with 140 mL of
2N NaOH solution. A solution of di-teft-butyl dicarbonate (60.2 g, 0.276 mol)
in 180 mL of THF was then added dropwise over 1 h to the rapidly stirred
solution. The reaction mixture was then allowed to warm to room temperature
and was stirred an additional 18 hours. The THF was then removed under
reduced pressure and the remaining aqueous slurry was brought to pH 3 by
addition of 150 mL of 1M H 2 S0 4 solution. This was then extracted with ethyl
acetate (300 mL, 100 mL) and the combined organic layers were washed with
H2O (2X) and brine. The organic portion was dried over Na2SC>4 and
concentrated to give tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate as a colorless
oil (47.1 g).
PartB
A rapidly stirred solution of ter/-butyl 2-(2-
hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CH 2 C1 2
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Part A
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was cooled to 0°C under N 2 and treated with triethylamine (48.0 mL, 0.345 mol).
Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over
30 min. The reaction mixture was then allowed to warm to room temperature
and was stirred an additional 22 hours. The reaction was quenched by addition
5 of 500 mL saturated NaHC03 solution and the organic layer was separated. The
organic phase was then washed with H 2 0 (3 X 500 mL) and brine. The organic
portion was dried over Na 2 S0 4 and concentrated to give 2-{2-[(ferf-
butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
10 PartC
A stirred solution of 2-{2-[(ter?-butoxycarbonyl)amino]ethoxy}ethyl
methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide
(DMF) was treated with NaN 3 (16.1 g, 0.247 mol) and the reaction mixture was
heated to 90°C under N 2 . After 5 hours, the solution was cooled to room
1 5 temperature and treated with 500 mL of cold H 2 0. The reaction mixture was
then extracted with Et 2 0 (3 X 300 mL). The combined organic extracts were
washed with H 2 0 (4 X 100 mL) and brine (2 X 100 mL). The organic portion
was dried over MgS04 and concentrated to give 52.0 g of tert-butyl 2-(2-
azidoethoxy)ethylcarbamate as a light brown oil.
20
PartD
A solution of tert-bvdyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204
mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H 2 (3
Kg/cm 2 ) for 24 hours. The solution was then filtered through a CELITE pad and
25 concentrated to give 35.3 g of crude fert-butyl 2-(2-aminoethoxy)ethylcarbamate
as a colorless liquid that was used without further purification.
PartE
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500
30 mL of anhydrous CH 2 C1 2 , under N 2 , was treated with triethylamine (43 mL,
0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After
stirring overnight, the reaction mixture was washed with H 2 0 (2 X 300 mL) and
brine (300 mL). The organic portion was dried over Na 2 S0 4 and concentrated to
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give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave
43.6 g of tert-butyl 2-{2-[(3-iutroquinolin-4-yl)amino]ethoxy}ethylcarbamate as
bright yellow crystals.
5 PartF
A solution of tert-butyl 2-{2-[(3-nitroquinolin-4-
yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with
1 .5 g of 5% Pt on carbon and shaken under H 2 (3 Kg/cm 2 ) for 24 hours. The
solution was then filtered through a Celite pad and concentrated to give 6.92 g of
10 crude tert-butyl 2- {2-[(3-aminoqumolin-4-yl)amino]ethoxy}ethylcarbamate as a
yellow syrup.
Part G
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-
15 yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5 mmol) in 250 mL of anhydrous
CH 2 C1 2 was cooled to 0°C and treated with triethylamine (4.18 mL, 30.0 mmol).
Methoxypropionyl chloride (3.30 mL, 30.3 mmol) was then added dropwise over
5 min. The reaction was then warmed to room temperature and stirring was
continued for 1 hour. The reaction mixture was then concentrated under reduced
20 pressure to give an orange solid. This was dissolved in 250 mL of EtOH and
12.5 mL of triethylamine was added. The mixture was heated to reflux and
stirred under N 2 overnight. The reaction was then concentrated to dryness under
reduced pressure and treated with 300 mL of Et 2 0. The mixture was then
filtered and the filtrate was concentrated under reduced pressure to give a brown
25 solid. The solid was dissolved in 200 mL of hot methanol and treated with
activated charcoal. The hot solution was filtered and concentrated to give 11.1 g
of ?e/t-butyl2-{2-[2-(2-methoxyethyl)-liy-imidazo[4,5-c]quinolin-l-
yl]ethoxy}ethylcarbamate as a yellow syrup.
30 PartH
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-liy-imidazo[4,5-
c]quinolin-l-yl]ethoxy}ethylcarbamate (10.22 g, 24.7 mmol) in 250 mL of
CHCI3 was treated with 3-chloroperbenozic acid (77%, 9.12 g, 40.8 mmol).
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After stirring 30 minutes, the reaction mixture was washed with 1% Na 2 C03
solution (2 X 75 mL) and brine. The organic layer was then dried over Na 2 S0 4
and concentrated to give 10.6 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-
li/-imidazo[4,5-c]quinolin-l-yl]ethoxy}ethylcarbamate as an orange foam that
was used without further purification.
Parti
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-l J £f-
imidazo[4,5-c]quinolin-l-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) in 100
mL of 1,2-dichloro ethane was heated to 60°C and treated with 10 mL of
concentrated NH 4 OH solution. To the rapidly stirred solution was added solid p-
toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 minute period. The
reaction mixture was treated with an additional 1 mL concentrated NH 4 OH
solution and then sealed in a pressure vessel and heating was continued for 2
hours. The reaction mixture was then cooled and treated with 100 mL of CHCI3.
The reaction mixture was then washed with H2O, 1% Na2CC>3 solution (2X) and
brine. The organic portion was dried over NaaSC>4 and concentrated to give 10.6
g of tert-butyl 2- {2-[4-amino-2-(2-methoxyethyl)- l/f-imidazo[4,5-c]quinolin- 1 -
yl]ethoxy}ethylcarbamate as a brown foam.
Part J
Tert-butyl 2- {2-[4-amino-2-(2-methoxyethyl)-l//-imidazo[4,5-
c]quinolin-l-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) was treated with 75
mL of 2M HC1 in ethanol and the mixture was heated to reflux with stirring.
After 1.5 hours, the reaction mixture was cooled and filtered to give a gummy
solid. The solid was washed with ethanol and Et 2 0 and dried under vacuum to
give the hydrochloride salt as a light brown solid. The free base was made by
dissolving the hydrochloride salt in 50 mL of H 2 0 and treating with 1 0% NaOH
sohition. The aqueous suspension was then concentrated to dryness and the
residue was treated with CHCI3. The resulting salts were removed by filtration
and the filtrate was concentrated to give 3.82 g of 1 -[2-(2-aminoethoxy)ethyl]-2-
(2-methoxyethyl)-lJy r -imidazo[4,5-c]quinohn-4-amine as a tan powder.
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MS 330 (M + H) + ;
^NMRpOO MHz, DMSO-J tf ) 5 8.10 (d, J= 8.1 Hz, 1 H); 7.66 (d, J= 8.2 Hz,
1 H); 7.40 (m, 1 H); 7.25 (m, 1 H); 6.88 (br s, 2 H); 4.78 (t, /= 5.4 Hz, 2 H);
3.89 (t, J = 4.8 Hz, 2 H); 3.84 (t, J = 6.9 Hz, 2 H); 3.54 (t, J = 5.4 Hz, 2 H); 3.31
5 (s, 3 H); 3.23 (t, J = 6.6 Hz, 2 H); 2.88 (t, J= 5.3 Hz, 2 H).
PartK
Under a nitrogen atmosphere, a suspension of l-[2-(2-
aminoethoxy)e1hyl]-2-(2-meUioxyeu^
10 (140.5 mg, 0.428 mmol) in a mixture of dichloromethane (3.5 mL) and
triethylamine (150 uL, 1 .07 mmol) was cooled to 0°C. Palmitoyl chloride (130
oL, 0.428 mmol) was slowly added. The reaction mixture was allowed to stir at
0°C for 2 hours at which time analysis by thin layer chromatography indicated
that there was no starting material left. The reaction mixture was diluted with
1 5 dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (2
x 5 mL), dried over magnesium sulfate and then concentrated under reduced
pressure. The resulting residue was purified by column chromatography (12 g of
silica gel eluted with 2% methanol in dichloromethane) to provide 183 mg of 7Y-
(2-{2-[4-amino-2-(2-methoxyethyl)-l/^-imidazo[4,5-c]quinolin-l-
20 yl] ethoxy} ethyl)hexadecanamide as a white powder.
Anal. Calcd for €33^3^03: %C, 69.80; %H, 9.41; %N, 12.33; Found: %C,
69.60; %H, 9.28; %N, 11.99.
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Example 2
Preparation of jV-(2-{2-[4-amino-2-(2-methoxyethyl)-
1 H-imidazo [4 , 5 -c] qiiinolin- 1 -yl] ethoxy } ethyl) octadecanamide
5
Under a nitrogen atmosphere, a mixture of l-[2-(2-aminoethoxy)ethyl]-2-
(2-methoxyethyl)-l J ftT-imidazo[4,5-c]quinolin-4-amine (442.6 mg, 1.344 mmol)
in a mixture of dichloromethane (20.0 mL) and triethylamine (468 uL, 3.56
10 mmol) was cooled to 0°C. Stearoyl chloride (454 ^L, 1 .34 mmol) was slowly
added over a period of 10 minutes. The reaction mixture was allowed to stir at
0°C for 1 hour at which time analysis by thin layer chromatography indicated
that there was no starting material left. The reaction mixture was diluted with
dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (2
15 x 1 5 mL), dried over magnesium sulfate and then concentrated under reduced
pressure. The residue was dried under high vacuum to provide 834 mg of crude
product. The crude product was purified by column chromatography (20 g of
silica gel eluted with 2% methanol in dichloromethane) to provide 596 mg of
product. This material was recrystallized from ethyl acetate (1.2 mL) and then
20 further purified by column chromatography (25 g of silica gel eluted sequentially
with 300 mL of 1% CMA (80% chloroform/18% methanol/2% ammonium
hydroxide) in chloroform, 500 mL of 2% CMA in chloroform, 500 mL of 3 %
CMA in chloroform, 500 mL of 4 % CMA in chloroform, 750 mL of 5 % CMA
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in chloroform, and 500 mL of 6 % CMA in chloroform) to provide 23.8 mg of
A^-(2-{2-[4-amino-2-(2-methoxyethyl)-l/r-imidazo[4,5-c]quinolin-l-
yl]ethoxy}ethyl)octadecanamide as a white waxy solid, m.p. 80-83°C.
Anal. Calcd for CssH^NsOa • 0.694% H 2 0: %C, 70.06; %H, 9.65; %N, 11.67;
5 Found: %C, 70.60; %H, 9.91; %N, 1 1.46.
Example 3
Preparation of JV-(2- {2-[4-amino-2-(2-methoxyethyl)-
1 #-imidazo [4, 5 -c] quinolin- 1 -yl] ethoxy } ethyl)do dec anamide
Under a nitrogen atmosphere, a mixture of l-[2-(2-
aminoethoxy)ethyl]-2-(2-memoxyethyl)-li/-imidazo[4,5-c]quinolin-4-ainine
(527.0 mg, 1.600 mmol) in a mixture of dichloromethane (20.0 mL) and
15 triethylamine (551 uL, 4.00 mmol) was cooled to 0°C. Lauroyl chloride (370
U.L, 1.60 mmol) was slowly added over a period of 10 minutes. The reaction
mixture was allowed to stir at 0°C for 1 hour at which time analysis by thin layer
chromatography indicated that there was no starting material left. The reaction
mixture was diluted with dichloromethane (50 mL), washed with saturated
20 sodium bicarbonate solution (2x15 mL), dried over magnesium sulfate and then
concentrated under reduced pressure. The residue was dried under high vacuum
to provide 821 mg of crude product. The crude product was purified by column
chromatography (20 g of silica gel eluted with 2% methanol in dichloromethane)
to provide 527 mg of product. This material was recrystallized from ethyl acetate
25 (1 .2 mL) and then further purified by column chromatography (25 g of silica gel
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eluted sequentially with 300 mL of 1% CMA in chloroform, 500 mL of 2%
CMA in chloroform, 500 mL of 3 % CMA in chloroform, 500 mL of 4 % CMA
in chloroform, 750 mL of 5 % CMA in chloroform, 750 mL of 6 % CMA in
chloroform, 500 mL 100% CMA) to provide 22.4 mg of 7V-(2- {2-[4-amino-2-(2-
5 memoxyethyl)-l/f-imidazo[4,5-c]quinolin-l-yl]ethoxy}ethyl)dodecanamide as a
white waxy solid, m.p. 80-83°C.
Anal. Calcd for CagH^NsOa • 1.66% H 2 0: %C, 66.94; %H, 8.90; %N, 13.46;
Found: %C, 66.94; %H, 9.37; %N, 13.28.
1 5 Under a nitrogen atmosphere, a mixture of l-[2-(2-aminoethoxy)ethyl]-2-
(2-methoxyethyl)-lijT-imidazo[4,5-c]quinolin-4-amine (444.5 mg, 1.349 mmol)
in a mixture of dichloromethane (20.0 mL) and triethylamine (470 uL, 3.37
mmol) was cooled to 0°C. Myristoyl chloride (367 uL, 1 .35 mmol) was slowly
added over a period of 1 0 minutes. The reaction mixture was allowed to stir at
20 0°C for 1 hour at which time analysis by thin layer chromatography indicated
that there was no starting material left. The reaction mixture was diluted with
dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (2
x 1 5 mL), dried over magnesium sulfate and then concentrated under reduced
pressure. The crude product was purified by column chromatography (20 g of
25 silica gel eluted with 2% methanol in dichloromethane) followed by
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recrystallization from ethyl acetate (1.2 mL) and then further purified by column
chromatography (25 g of silica gel eluted sequentially with 300 mL of 1% CMA
in chloroform, 500 mL of 2% CMA in chloroform, 500 mL of 3 % CMA in
chloroform, 500 mL of 4 % CMA in chloroform, 750 mL of 5 % CMA in
5 chloroform, and 600 mL of 6 % CMA in chloroform) to provide 9.5 mg of JV-(2-
{2-[4-amino-2-(2-metiaoxyethyl)-liy-imidazo[4,5-c]quinolin-l-
yl]ethoxy}ethyl)tetradecanamide as a white waxy solid, m.p. 85-87°C.
Other Exemplary Compounds
10 Certain other exemplary compounds have the Formula (VDI-X) and the
following substituents, wherein each line of the table represents a specific
compound of Formulas VIII, XI and/or X as indicated by the entry in the first
column.
15
20
X
25
Formulas
Ri-i
R>
0
L
VIII, X
-(CH 2 )ioCH 3
H
-(CH 2 ) 3 -
-NHC(O)-
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VIII IX X
//-iTT \ / — '"r_r
"S^ 2 | 3 "
-NHC(O)-
VIII IX X
—
—
-(CH 2 ) 3 -
-NHC(O)-
-(CH2)lsCH3
-(CH 2 ) 3 -
-INIjA^vJ )-
VIII IX X
fr*X-X \ f^T-T
~ ( v-Jti2 ) 1 8 l^.tt.3
^
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )5CH3
—
-(CH 2 )3-
VIII, IX, X
-(CH2)7CH=CH(CH2)7CH3
—
—
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
—
~rr^r\ 3 ~
-NHC(O)-
VIII, IX, X
-^i±2)6(y^cl2^tl— CJtl J 3 Cri 2 Url 3
//-'TJ" "\ /T^TJ- /-1TJT_ /-1TT\ /pU \ / 1TJT
—
"rrTT^ 3 "
-NHC(O)-
— VIII, X —
.'PI T \ /- rr
-(Cli2.hoO.ti3
rw
"fPTT 2 \ 3 " '
— "L,t" —
-NHC(O)-
VIII, IX, X
-(CH 2 )i 2 CH 3
"FtJ 3
-(CH 2 ) 3 -
VIII, IX, X
-(CH2)l4CH3
nxi
-(CH 2 )3-
-NHC(O)-
VIII, IX, X
-(CH 2 )i6CH 3
~f»
-(CH 2 )3-
VIII, IX, X
-(CH 2 ) 1S CH 3
~rrf
"T^j
-(CH 2 ) 3 -
Ktxxr^/r\\
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )5CH 3
-CH3
-(CH 2 ) 3 -
~KTXXt^ffW
-iN_riv^^Li )-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )7CH3
-(CH 2 )3-
>jxxc*/fV\
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)2(CH 2 )4CH3
nx^
: CH I
— i^ 2 x 3 " —
-iNJnL^^LJ )-
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 3 CH 2 CH3
-(CH 2 )3-
-NHC(O)-
VIII, IX, X
-(CH 2 ) 2 (CH2CH=CH)4(CH 2 )4CH3
CH
-(CH 2 )3-
t<nxcfcw
— VIII, X ^
-(CH 2 )ioCH 3
nn nTT
-CH2CH3
-(CH 2 ) 3 -
-1N±H_ \VJ )-
VIII, IX, X
_ (CH 2 )i2CH3
-CH2CH3
-(CH 2 )3-
XEE' ^
-(CH 2 ) 14 CH 3
-CH2CH3
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) 16 CH 3
-CH 2 CH3
-(CH 2 ) 3 -
-NHC(O)-
VIII IX X
-(CH 2 )i 8 CH 3
-CH 2 CH3
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
fr^tx \ r^x-x — r^xxtr^xx ^ r*xx
-CH 2 CH 3
f^ 2 \ 3 "
-NHC(O)-
-(Lxli J 7 LJHL— ^rl^rl2
-CH2CH3
-NHC(O)-
vin ix x
-^M 2 j 6 ^tl 2 (^tl~OJrl ) 2 (^JbL 2- )4l^rl3
-CH 2 CH 3
(CH)
-NHC(O)-
VIII IX X
-^Jrl 2 )6i.^Jti2^ii— l^rt J3^xl 2 ^ Jfl 3
-CH2CH3
"phT"
-NHC(O)-
VIII, IX, X
tr^xx \ //~*xx t^xx— c*x x\ /t^tt \ c^xx
-((_H.->)-.(V H-,V ,1 1— t -I 1 )4(t, U. 2 ) 4 i... ! I3
-CII2CH3
-(CH 2 ) 3 -
-NHC(O)-
/^t^ 2 \ 10 ^!j 3
-(CH-)) 2 CH 3
-NIIC(O)-
■ —
VIII, IX, X
-(CH 2 ) 12CH3
"(CH 2 )2CH3
"rrrqn 3 "
-NHC(O)-
VIII, IX, X
-(CH2) 14CH3
*Trrj\
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH2)i6CH 3
-(CH 2 )2CH 3
-(CH 2 )3-
-INll^^C )-
VIII, IX, X
-(CH 2 )i8CH3
//-ITT \ /""ITT
-(CH 2 ) 3 -
-NHC(O)-
VTII, IX, X
-(CH 2 )7CH=CH(CH 2 )5CH 3
-\\ J rl2)2^XX3
-(CH 2 )3-
Ktrxcfrw
VIII, IX, X
-^v_,±l2j7<-rl— *^rl^rl2j7^-il3
-^Xl 2> l2v-'-tl3
— il^T^ 3 " —
vrpj/-'/ (~\\
-INJnL^ \ \J)-
VIII, IX, X
-(CH2)6(CH2CH=CH)2(CH2)4CH3
-(CH 2 ) 3 -
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH) 3 CH 2 CH 3
-(CH 2 ) 2 CH3
-(CH 2 )3-
-INxlv^^w J-
VIII, IX, X
-(Ott 2 ) 2 V^^2^ii— Cri M^-ra^CH^
-^^Xl 2 ^ 2 v---tl3
-(CH 2 )3-
-NHC(O)-
— VIII, x —
-(CH 2 )ioCH3
/ ' It 1 V ' I I I'll
-1NI1v-'( i vJ )-
VIII, IX, X
-(CH 2 )i2CH3
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH2)l4CH3
P'TT /-vf~*U r ' 11
-(CH 2 ) 3 -
VIII, IX, X
/ r ■ I 1 \ / ' I 1
/■if 1 \[ '|i r ■ ii
S^ 2 \ 3
-NHC(O)-
VIII, IX, X
-(CH 2 )i8CH 3
-(01-12)3-
Knxcfrt^
-irirlK^yyJ )-
VIII, IX, X
-(CH2)7CH=CH(CH 2 )5CH 3
-(CH 2 )3-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )7CH3
r*xx t~tcxx cit
-^Xl 2 v-'^-'Xl2»^-rl3
-(CH 2 ) 3 -
VIII, IX, X
-(CH 2 )g(CH2CH=CH)2(CH2)4CH3
I '1 1 f \j 'II /-ITT
-CJtl2>_>Url 2 L,xl3
-(CH 2 )3-
VIII, IX, X
-(CH 2 ) S (CH 2 CH=CH) 3 CH 2 CH3
-CH 2 OCH2CH 3
-(CH 2 ) 3 -
-(CH 2 ) 2 (CH2CH=CH)4(CH2)4CH3
/ ^ 11 P7P'T T ( ' I I
-V_ i7l27_/L^i I71L ll_|
-(CH 2 ) 3 -
-INJtl^^w )-
V1 ^ I I ; I ^ X
-(CH 2 )iOCH 3
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH 2 )i2CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-CCH 2 ) I4 CH 3
-(CH 2 ) 2 OCH3
-fCH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-fCH 2 ) 16 CH 3
-(CH 2 ) 2 OCH 3
-fCH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH2)l8CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH,) 7 CH=CH(CH 2 ) 5 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(O)-
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-(CH2) 7CH— CH(CH 2 )7CH 3
/^TJ 2 ^ 3
-NHC(O)-
vni ix' x~
-(CH 2 )6(CH 2 CH=CH) 2 ( CH 2 )4CH 3
/p»T_T \ ApTT
-((_H 2 ) 3 -
-NHC(O)-
VIII IX X
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH2)2(CH2CH=CH)4(CH2)4CH3
/piT \ p\p"nqr
-(CH 2 ) 3 -
-NHC(O)-
— VIII, x —
-(CH 2 )ioCH 3
4_-rl2 J 3 ^3
— i^^ 3 " —
-NHC(O)-
VIII, IX, x
-(CH 2 )i2CH 3
/r>TT \ pTT
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH 2 )hCH3
(C^Vf \ I^TT
- ^ L^rl2 73
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH 2 )i 6 CH 3
-(CH 2 ) 3 -
VIII, IX, X
-(CH 2 ) 18 CH 3
-(CH 2 )3CH 3
-(CH 2 ) 3 -
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )5CH3
1^tj 2 \ 3
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH2)7CH 3
~(CH 2 ) 3 CH3
-(CH 2 ) 3 -
-IN \J )-
VIII, IX, X
-(CH 2 )6(CH2CH=CH) 2 (CH2)4CH 3
/pa "\ pij
-(CH 2 ) 3 -
-NHC(O)-
VIII, IX, X
-(CH 2 )<5(CH 2 CH=CH) 3 CH 2 CH 3
/P^TT \ pTT
-(CH 2 ) 3 CH 3
— i^ 2 x 3 " —
~\nxe~>{(~\\
VIII, IX, X
-(CH2)2(CH2CH=CH)4(CH 2 )4CH3
-(CH 2 ) 3 CH 3
-(CH 2 ) 3 -
-INllv^U )-
— VIII, x —
-(CH 2 )ioCH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 )i2CH 3
w
==
-(CH 2 ) 4 -
VIII, IX, X
-(CH 2 )hCH 3
2
VIII, IX, X
-(CH2)i6CH 3
"(CH 2 ) 4 "
/UttV
-NHC(O)-
VIII, IX, X
-(CH 2 )isCH 3
XT
^
-(CH 2 )4-
Krxxr^td^
-Lsxiy^yyj )-
VIII, IX, X
-(CH 2 )7CH=CH(CH2)sCH 3
—
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH2)7CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
fr^xj \ frxx r*xx—r*xx\ tr^xx \ r*xx
-(Lr± 2 )6(t_,rl 2 CJtl— t_±i J 2 (^rl 2j )4l_.tl 3
tt
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)3CH 2 CH 3
—
—
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(Cn 2 ; 2 (CJd^(_.ti— Ciij4(l_J:i 2 )4Cll3
-(CH 2 ) 4 -
-NHC(O)-
— VIII, x —
-(CH 2 )ioCH 3
PT4
-(CH 2 ) 4 -
-NHC(O)-
-(CH2)i 2 CH 3
"73T
-NHC(O)-
VIII IX X
cr^xx \ r^Tj
-(K^tln) l4<~Jtl 3
T^rT
-CH 3
~rcH) 4 ~
-NHC(O)-
fr~xx \ c*xx
ffxt (
-NHC(O)-
VIII IX X
fr~xx \ r^xx
= CH 3
-(CH 2 )4-
-NHC(O)-
VIII, IX, X
fr^xx \ r^xx — c*xx{(~*xx \ r^xx
-[tn 2 )7LH- •_Jtm_rl 2 j5l_ll3
Ti^
-(CH 2 ) 4 -
-NIIC(O)-
VIII, IX, X
fr^xx \ rxx—c^xxfrxx ~\ cxx
-(CM 2 )7CH— Crl(Crl 2 j7CJtl3
Ti^r
"^tPn""
-NHC(O)-
VIII, IX, X
//"'TT \ /rrr /TJ— f~<TX\ ff^XX \ f~^XX
: nTO
-NHC(O)-
VIII, IX, X
ft >tt \ fr-^xx f~ y xx—t~ i xj\ cxx r*xx
737
crn \*~
-NHC(O)-
VIII, IX, X
ft itt \ /PIT rXX—(~*XX\ (C~XX \ CXX
CH^
"rr-TT^ 4 "
-NHC(O)-
— vnI ' x —
-(CH2)loCH3
/-tj rAj
-CH2CH 3
cm\
-NHC(O)-
VIII, IX, X
-(CH 2 )i 2 CH 3
pu\
VIII, IX, X
-(CH 2 )i4CH 3
CH 2 CH 3
— i^ 2 \ 4 " —
-NIIC(O)-
VIII, IX, X
-(CH 2 )i6CH 3
~PTT 2 r TT 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
ffXX \ /~opr
CH Z CH 3
-NHC(O)-
VIII, IX, X
fr^xx \ r^xx—r^xxtrxx \ cxx
VhVh 3
"rrn 2 . 4 "
-NHC(O)-
/pTj \ r^xx— r^xxtr^xx ^ cxx
-^n 2 j7V_-xi— drH i dl 2 j7dl3
"ci^CH 3
fc^n \ ~
-NHC(O)-
Vlll' IX A~
frxx \ {(~*xx c*xx—t~ i xx\ fcxx \ r*xx
CH 2 CH 3
rrvf\
-NHC(O)-
\TTTT TV V
f f 11 \ / f °l] ( 1 1 1 f'l[\ / 1 [ I ( 1 ! 1
-{K^tl2)6\ y^xl2*~-xl~ j3^rl2Cn-3
"ci/cH 3
"rPH 2 . 4 "
1pp\
-NHC(O)-
VIII, IX, X
"c^CH 3
"1^2)4-
-NHC(O)-
— VIII, x —
-tCli 2 )io*--H. 3
(cxx ^ nix
-NHC(O)-
VIII, IX, X
-(Ctl2)i 2 drl 3
fcxx ^ ctx
"rrK 2 . 4 "
-NHC(O)-
VIII, IX, X
-^C-rl 2 )i4dl 3
fr^xx "\ opt
-^xl 2 ) 2 dl 3
"rrrj 2 | 4 "
-NHC(O)-
VIII, IX, X
-(CH 2 )i6CH 3
(C^XX \ C^XX
-\\,r\2)2^£X3
crvf\ 4 '
-NHC(O)-
VIII, IX, X
-(CH 2 )isCH 3
-(CH 2 ) 4 -
VIII IX X
-(CH 2 )7CH=CH(CH 2 )5CH 3
.(CH Z ) 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 ) 7 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) S (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
vni, ix, x
-(CH2)6(CH 2 CH=CH) 3 CH 2 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-fCH2) 2 (CH2CH=CH) 4 CCH 2 ) 4 CH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, X
-(CH 2 ) 10 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
-39-
WO 2005/018555
PCT7US2004/026157
VIII IX X
-(CH 2 )i 2 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 )4-
-NHC(O)-
VIII IX X
-(CH 2 )i4CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-y^xL2l 16^-^-3
-CH2OCH2CH3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 )i 8 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 7 CH=CH(CH 2 )5CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 7 CH=CH(CH 2 )7CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 6 (CHoCH=CH) 2 (CH 2 ) 4 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 )6(CH 2 CH=CH)iCH->CH 3
-CH 2 OCH 2 CH 3
-(CH 2 )4-
-NHC(O)-
VIII IX X
-(CH 2 ) 2 (CH2CH=CH)4(CHi)4CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(O)-
-(CH 2 ) 10CHU
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 )i2CH-
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(O)-
-(CH->) 14CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 2 OCH 3
_(CH 2 ) 4 -
-NHC(O)-
\7TTT TY V
Vlll, 1A., A
-(CH 2 )7CH=CH(CHt)5CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 ~
-NHC(O)-
\;tti IV V
V 111, 1A_, J\
-(CHi)7CH=CH(CH 2 )7CH 3
-(CH 2 )70CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CHi)4CH 3
-(CH 2 ) 2 OCH 3
_(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 )6(CH 2 CH=CH) 3 CH 2 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CHo) 2 (CH-)CH=CH)4(CH 2 ) 4 CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 ~
-NHC(O)-
/pti n pur
-(CH 2 ) 3 CH 3
_(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-(CH 2 ) 12CH3
-(CH 2 ) 4 -
-NIIC(O)-
VIII IX X
_(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
-^n 2 jlfi^n3
\^s.X2J3^ ±x 3
-(CH 2 ) 4 -
-NHC(O)-
VIII IX X
1S>-113
1^"2;3^J13 —
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )sCH 3
_(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH9) 7 CH=CH(CH-3)7CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-MIC(O)-
VIII, IX, X
-(CH 2 ) fi (CH,CH=CH) ? ( CIL ) 4 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(O)-
VIII, IX, X
-(CH 2 )6(CH-,CH=CH) 3 CH2CH3
-CCBU^CH*
-(CH 2 ) 4 -
-NIIC(O)-
VIII IX X
-(CII 2 ) 2 (CTI-,CII=CH)4(CHo)4CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(O)-
-(CH 2 ) 10 CH 3
H
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CHo)i 2 CH 3
H
-(CH 2 )5-
-NIIC(O)-
VIII IX X
-(CH?) 14 CH 3
H
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
fPH \ ,(TI.
-(CH 2 )s-
-NHC(O)-
VIII IX X
-^ii 2 » 18*^113
H
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 ) 7 CH=CH(CH2)5CH 3
H
_(CH 2 )5-
-NHC(O)-
VIII IX X
-(CH 2 )7CH=CH(CH 2 ) 7 CH 3
H
-(CH 2 ) 5 -
-NHC(O)-
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
H
-(CH 2 ) 5 -
-NHC(O)-
VIII IX, X
-(CH 2 )6CCH 2 CH=CH)3CH 2 CH 3
H
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 ) 2 (CH 2 CH=CH) 4 (CH?)4CH 3
H
-(CH 2 ) 5 -
-NHC(O)-
~{V^ri2) 10*^^3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-(CH 2 )i 2 CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-^n 2 ll4<^ri 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-^n 2 ji5^n. 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
A^'- n 2/18 v -'- n 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )sCH 3
-CH 3
_(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )7CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 ) S (CH 2 CH=CH) 2 (CH7)4CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 ) S (CH 2 CH=CH) 3 CH 2 CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 )2(CH 2 CH=CH)4(CH->)4CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, X
-(CH 2 )i 0 CH 3
-CH 2 CH 3
-(CH 2 ) S -
-NHC(O)-
VIII, IX, X
-(GH 2 ) I2 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) 14 CH 3
-CH 2 CH 3
-CCH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-{•CH 2 ) 16 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-(CH2), 8 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
-40-
WO 2005/018555
PCT7US2004/026157
vm, ix, x
-(CH 2 )7CH=CH(CH9 , )7CH3
-CH2CH3
-(CH 2 )5-
-NHC(O)-
VIII IX X
-(CH 2 )ts(CH 2 CH=CH)2(CH-,\CHi
~^^ S
-NHC(O)-
VIII IX X
-(CH2)6(CH 2 CH=CH) 3 CfL CH3
CH 2 CH 3
-NHC(O)-
VIII IX X
-(CH2) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH 3
CRCH
-NHC(O)-
VIII, X
-(CH 2 )ioCH 3
-(CH 2 )iCH 3
-(CH 2 )s-
-NHC(O)-
VIII IX X
-(CH 2 ) 2 CH3
-NHC(O)-
VIII, IX, X
-(CH 2 )i4CH 3
-(CH 2 ) 2 CH3
-(CH 2 )5-
-NHC(O)-
VIII IX X
-(CH 2 }l6CH3
-(CH 2 ) 2 CB[3
-NHC(O)-
VIII, IX, X
-(CH 2 )i8CH 3
-(CH 2 )->CH 3
"rPM^ 5 "
/nnf
-NHC(O)-
VIII IX X
-(CH->)7CH=CH(CH2)sCH3
-(CH 2 ) 2 CH 3
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )7CH3
.(Cjj 2 ) 2 CH 3
-(CH 2 )5-
-NHC(O)-
VIII IX X
-(CH2)6(CH 2 CH=CH) 2 (CH-;)4CH3
-(CH 2 )2CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 )6(CH 2 CH==CH) 3 CH2CH3
-(CH 2 ) 5 -
VIII IX X
-(CH2) 2 (CH 2 CH=CH)4(CH-))4CH3
-(CH2) 2 CH 3
"rPH 2 ^"
-NHC(O)-
-(CH 2 )ioCH 3
"/r-Tj^ 5 "
VIII, IX, X
"^u 2 ^ 12 ^ 3
-CH-)OCH 2 CH 3
-(<-.H 2 ; 5 -
-NHC(O)-
VIII IX X
-(•-■ti2.h4C.tl3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
_pw..nPTT„pw,
-*—n 2 v^v^xa 2 ^ji 3
-(CH 2 ) S -
-NHC(O)-
VIII IX X
-(CH 2 )7CH=CH(CH2)5CH 3
-CH->OCH 2 CH 3
-(CH 2 ) S -
VIII, IX, X
-(CH2)7CH=CH(CH 2 )7CH 3
-CH2OCH2CH3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-(CHi)6(CH2CH=CH)2(CH 2 )4CH 3
PTT-.nPTT^PTT,
-(CH 2 ) 5 -
-NHC(O)-
VIII IX X
-(CH 2 ) 6 (CH9CH=CH) 3 CH 2 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHC(O)-
VIII, IX, X
-PH-,OPH,PH,
-i^xa 2 uv^xa 2 ^xa 3
-NHC(O)-
VIII, X
-(CH 2 )ioCH 3
-(CH 2 ) 2 OCH 3
-(CH 2 )s-
-NHC(O)-
-(CH 2 )i2CH3
-CPH^VOPH-,
\^^ 1 2/2^ J ^ rl 3
-NHC(O)-
VIIl' DC X
-(CH-) 14 CH 3
-(CH 2 )->OPH 3
-(CTf^ir-
-^"■2)5-
-NHC(O)-
VIII IX X
- (CH?) 16CH3
\\^ n 2)2^^ I:1 3
-NHC(O)-
VIII IX X
_(CH,) 18 CH 3
-(CH 2 ) 2 OCH 3
-fPTT.,1*-
-NHC(O)-
VIII, IX, X
-(GHUyCH - CH(CH9) 5 CH 3
-(CH 2 ) 2 OCH 3
-NHC(O)-
VIII IX X
-(CH2)7CH=CH(CH2)7CH 3
-(CH->) 2 OCH 3
"fPH 2 \ 5 "
-NHC(O)-
VIII IX X
-(CH 2 )6(CH2CH=CH) 2 (CH 2 ) 4 CH3
-(CH?) 2 OCH 3
(CH)
-NHC(O)-
vni ix x
-(CH 2 )6(CH2CH=CH)3CH 2 CH3
-(CH2)20CH 3
"rprn"
-NHC(O)-
VIII IX X
-(CH2)2(CH 2 CH=CH) 4 (CHn) 4 CH3
-(CH 2 )20CH 3
(rvi \ "
-NHC(O)-
-(CH2)ioCH 3
-(CH 2 ) 3 CH 3
rr^r\
-NHC(O)-
VIII IX X
-V.CH.2jl2Ctl3
-(CH 2 )-CH 3
VIII IX X
-(CH z ) i4 CH 3
-(CH 2 ) 3 CH 3
rppn 5 "
-NHC(O)-
VIII IX X
-(,cri2h6Cri3
(cn.2;3Cri3
"rPFn
-NHC(O)-
VIII IX X
-(CH 2 )i8CH 3
-(CH 2 ) 3 CH 3
"frxj 2 { 5 "
-NHC(O)-
VIII IX X
-(CH2)7CH = CH(CH?)5CH 3
\^' n -2j3^ n 3
(CH)
-NHC(O)-
VIII IX X
-(CII 2 )7CH=CH(CH2)7CH 3
-(CH 2 ) 3 CH 3
fCTf^'
-NHC(O)-
VIII IX X
-(CH 2 )6(CH 2 CH=CH)-i(CH2)4CH3
-(CH 2 ) 3 CH 3
"(CH ) "
-NHC(O)-
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 3 CH-jCH 3
-(CH2) 3 CH 3
-(CH 2 )s-
-NHC(O)-
VIII, IX, X
-(CH 2 )2(CH2CH=CH)4(CH Z )4CH3
-(CH7) 3 CH 3
-(CH7>5-
-NHC(O)-
-NHC(O)-
VIII, IX, X
-(CH 2 )i 2 CH 3
g
-(CH 2 ) 2 0(CH7) 2 -
-NHC(O)-
VIII IX X
-(CH 2 )i4CH 3
—
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 )i6CH 3
—
—
-(CKU) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII IX X
-\\^r±2j i8^ri3
-(CH7) 2 0(CH 2 ) 2 -
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0>
VIII, IX, X
-(CH2) 7 CH=CH(CH 2 ) 7 CH 3
H
-(CH 2 )20(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) S (CH 2 CH=CH) 2 CCH 2 ) 4 CH 3
H
-(CH 2 ) 2 0(CH 2 )2-
-NHCfCO-
VIII, IX, X
-(CH 2 ) S (CH 2 CH=CH) 3 CH 2 CH 3
H
-(CH 2 )20(CH 2 )2-
-NHC(O)-
VIII, IX, X
-(CH 2 )2(CH 2 CH=CH) 4 CCH 2 ) 4 CH3
H
-(CH 2 )20(CH 2 )2-
-NHC(O)-
VIII, X
-(CH 2 )i 0 CH 3
-CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHCfO)-
-41-
WO 2005/018555
PCT7US2004/026157
VIII IX X
-^H2j2>-'l.*-'ll2j2-
-NHC(O)-
VIII, IX, X
-(CH2) 14CH3
/'ptt ~v i-vf'Tr \
-^n 2 ; 2 u^ii 2i ) 2 -
-NHC(O)-
vm, ix, x
-(CH2)l6CH3
~~Fw
-((_Jtl2j2U^Jtl2j2-
\7"FTT TV Y
V 111, IJv, .A
CTT
-(CH 2 )20(CH 2 )2-
-NHC(O)-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )5CH 3
"pTT
-^^H 2 J 2 ^-'^^ll2/2~
VIII, IX, X
-(CH2)7CH=CH(CH2)7CH 3
-NHC(O)-
-\y,ri.2)6\ V~'ll2 , -'tl— Cll ^2^tl2j4^1l3
"rrf 2
-NHC(O)-
VIII, IX, X
~PLJ^
-t«^H2j 2 L'^ii 2 j2~
-In 1 J ^( y_J )-
VIII, IX, X
-(CH2)2(CH2CH=CH)4(CH2)4CH 3
"pTT
SfTJ "\ Pi/PTT ^
-((_.il 2 ;2 , -'( t -'tl2 / )2-
-IN 1 1 v_l V' )-
— VIII, x —
-(CH 2 )i 0 CH 3
PTJ PTJ
-CH2CH3
/^T-j ~\ Pi/pTjr "\
-^l_-jtl 2 J 2 Ut L.la 2 ; 2 -
VIII, IX, X
-(CH2)i2CH 3
/PTT \ p\/pTT \
-^ll2j2 ( -'^J rl 2j2 -
o\_lVJ 1
VIII, IX, X
-(CH 2 )i4CH 3
ruPTT 3
-CH2CH3
/T^T-J ^ O/PU ^
-^H 2 J 2 ( -'V. , -'-tl2j2"
\"TTp/ /-»\
-INll^^Up
VIII, IX, X
-(CH 2 )i 6 CH 3
-CH2CH3
-(CH 2 ) 2 0(CH 2 ) 2 -
\ 1-1 / '/I lA
-.N iiv_i yj )-
VIII, IX, X
-(CH 2 )i 8 CH 3
-(Cll2j2*-'( < -'ll2;2-
Lv_l V/ )-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )5CH3
PHPTJ 3
-CH 2 CH 3
/PT_T \ pi/pur \
- \ 1 1 V ( ^ J )~
VIII, IX, X
-(CH 2 )7CH=CH(CH2)7CH 3
-^I_li2j2<-A<~<ll2;2"
-nilHU }
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH3
"rnW
-(LJti2,)2*~H ^112)2-
\7T r r' t (W
VIII, IX, X
jprj \ / f *tt t — ' V T- PI I\ pit ( ~ II
-(L/Jbl2jfi^tl2Crl— t_li J 3 L.ll 2 di3
ptt 3
- ^ <^ll2 12^1 ^H-2/2"
-T*JHC(0)-
vin, ix, x
-(CH2)2< CH2CH=CH)4(CH2)4CH 3
— ch'ch 3 —
t(~*VX \ Pl/'PTT ^
-(l^H2j 2 *-A*--'*l2j2~
-ISfHC(O)-
— VIII, x —
-(CH 2 ) 10 CH 3
/PIT \ pTT
-(CH 2 ) 2 CH 3
-\}^i±2)2 { ->v}—£i2)2~
MVTP '/Y"I\
VIII, IX, x
-(CH2) 12CH3
/r^T-T \ OTT
-(L.il2)2 < -'(.'-- J:1 2;2
-NHC(O)-
/Oil \ PT_T
/PT-T ^ PTT
-I, LJ^ 2 J2OXI3,
-(CH 2 ) 2 0(CH 2 )2-
-NHC(O)-
vin ix X
-(CH 2 ) 16 CH 3
/pTT \ pTT
"i.^112/2^'^ ^-'ll2/2~
-NHC(O)-
VIII IX X
-(L,i±2jl8^1l3
/OPT \ pTT
-(^t± 2 ) 2 V((-,tl2)2-
-NHC(O)-
VIII, IX, X
-(LJd.2J7L-.fcl— LJi(L.ti 2 j5Lll 3
/PTT PTT
-^^n 2 ^ 2 w^n 2 ^ 2 -
-NHC(O)-
/pu *\ pur— c^uxfc^Vl \ pu
-(LJd. 2 j7LJrl— L-ll(Lll2j7LJl3
/PTT^„PTT„
A^H272^-'v^'ll2^2
-NHC(O)-
VIII ix' X
//ITT \ /pTT /ITT PTJp. /pTT \ /"ITT
/"PTT PTT
cr , T-i "1 rifcvf \
-NHC(O)-
VIII IX X
-(Lli 2 j6l LJtl 2 LH— L/±i J 3 L II2LII3
/pTT-vpT-r.
-NHC(O)-
VIII, IX, X
/r»TT \ Z/TTT PIT PJT\ /PITT ^ fTT
-(Lll2j2(L I 1— I 1 i)4(L.li2 / )4^J-l 3
/PTT PTT
~ \ ^H 2 \ V^H 2 ^2
-NHC(O)-
VIII, X ^
-(L11 2 J io ( -'-"-3
-CH-) OCH^CH-i
-(CTI 2 )->0(CH-j) 2 -
-NIIC(O)-
VIII, IX, X
-(CH2J 12^113
PTT OPTT PT-T
-NHC(O)-
VIII, IX, X
-(CH2) 14CH 3
PTT OPTT PT-T
-^±i 2 j 2 ^<^ii 2 ; 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) ifiCH 3
-CH 2 OCH 2 CH 3
-(CHn iiU(CHj)i-
- N I 1 V_ 1 V V )-
VIII, IX, X
-(CH 2 )i8CH 3
PTT OPT-T PTT
- V^-"-2/2^--'\ ( "'- tl 2/2~
-NHC(O)-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 )sCH3
PTT OPT-T PT-T
-(\~-rt 2 )2{J\ ^--112/2-
vi-ir/pi\
- \ 1 n. 1 V ^ )-
VIII, IX, X
-(LJi 2 j7LJti— LJu(LJd 2 j7LJl3
PTT OPT-T PT-T
- 1 - n 2 w n 2 v--XT 3
^r^w ^ 0/(^11 1
~\ ^--112 /2*-'\ ^H-2/2
A I 1 V 1 V / 1
VIII, IX, X
-(CH 2 )6(CH2CH=CH)2(CH2)4CH 3
PT-T OPT-T PT-T
- Oil 2 ^ 0x12^^3
"V*-'ll2/2^'l *^H2/2 -
-NHC(O)-
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)3CH2CH 3
-CH2OCH2CH3
-(Cti 2 ) 2 U(Ul2)2-
VIII, IX, X
/"PUT 1 /PTT pit PTX\ /PTjr ^ P*Tjr
-(LJd 2 J 2 (LJ1.2LJi— Llij4(LJ1.7,)4LJi3
PT-T OPTT PT-T
-L^xa2^C-±l2^-tl3
-(CH 2 ) 2 0(CH2) 2 -
-NHC{0)-
— VI11 ' x —
-(CH2) 10CH3
/PTT ^ OPT-T
-^112 ^ii2j 2 -
VIII, IX, X
/pu \ po
-(CH2J12L-II3
/PTT > OPTT
-(CH2) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) 14CH3
/PTT ^ OPT-T
-V^-tl 2 )2^-'\}-' t *-2 )2~
-NHC(O)-
VIII, IX, X
-((_Jti 2 Ji6t--rl3
/PTT ^ OPTT
-(CH 2 )-iO(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH2J18CH3
/PTT > OPTT
0X12 J 2^ O1I3
/PT_T \ PVfTT A
-^li 2 )2*-J\ ^£12)2-
-NHC(O)-
VIII IX X
-(LJd 2 J 7 LJi— LJrl(V^ll2j5L-ll3
/PTT ^ OPT-T
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH2)7CH=CH(CH2)7CH3
/PTT ^ OPTT
-^^H 2 JT^\ ^'H2/2 -
-NHC(O)-
VIII, IX, X
-(CH2)6(CH2CH=CH) 2 (CH2)4CH 3
/OTJ ^ OPTT
-(OH2J2UUH.3
"(,^1^2^2^1^112/2-
VIII, IX, X
/PTJ \ /piT prj — PTJf\ PIT PIT
-( L-n 2 j6l^W2^n— 1^11 J3^ 112^113
/PTT ^ OPT-T
-^OXi2j2^0lT.3
"V ^ll2/2^'(^'H2/2~
-NHC(O)-
VIII, IX, X
-(CH2)2(CH2CH = CH)4(CH2)4CH3
/PT-T > OPTT
XT^Tr'/'^^^
-N1LV-\VJ )-
-(CH 2 ) 10 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) 12 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 )20(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 )„CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII, IX, X
-(CH 2 ) 16 CH3
-(CH 2 ) 3 CH 3
-(CH 2 )20(CH 2 )2-
-NHC(O)-
VIII, IX, X
-(CH 2 )i8CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(O)-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) S CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(O)-
-42-
WO 2005/018555
PCT7US2004/026157
\ PTTT TV V
Will, 1A, A
-(LJn. 2 )7Uii— CJ^(t^n. 2 )7Crl3
-(U/H 2 )301l3
- ( v^n.2 ^xi 2 )2
-NHC(O)-
VIII IX X
//~«tt ^ i'ptt ptt— ptt\ ^ptt \ rn.
-( ^ll2 / 6\ V-'H 2 t --'ll — ) 2 ( )4^'- n -3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(O)-
VIII IX X
/p^TT 'v (CU PTT— PTT i_PT4-PTT-
-| fIt Jrt(*w 112^11 V-'H ^3^X12^x13
-(CH2) 2 0(CH2) 2 -
-NHC(O)-
\/TTT TV V
V 111, 1A, A
/p^TT \ /p-"TT PH rHl /PTT ^ OH
-(CH 2 ) 3 CH3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(O)-
-(L,Jtl 2 ) 10^113
-(CH 2 )3-
-NHS(0) 2 -
ty y
-(LJ1 2 ) l 2 ^il3
^
-NHS(0) 2 -
— ix x —
-(v. 112)14^113
—
-(CH 2 )3-
-NHS(0) 2 -
\7TTT TV V
Vlll, JA, A
//^tjt ^ ptt
-(v_ili 2 ) i/,v •! l 3
—
—
1n!t"
-NHS(0) 2 -
VIII, IX, X
-(Cli 2 ) 18^*13
-NHS(0) 2 -
-vt
/p->ir \ prr— ptjvptt ^ ptt
-(l^li 2 )7^11 — L^lrl(CTrl 2 )5LJtl3
—
—
(CfJ^~
-NHS(0) 2 -
VIII, IX, X
//-iTT \ p-'tt— p^ttyptt *v
-(LJrl 2 )7^ii— (^,im^Jrl2)7*-ll3
"pit 2 , 3 "
-(^2)3-
-NHS(0) 2 -
VIII, IX, X
-(CH2)6(CH2CH=CH)2(CH2)4CH3
—
Imt"
-NHS(0) 2 -
VIII IX X
/ 1 — >t t \ i f '\ t prT pm-ia p^tt ptt
-(^ra 2 )6(t-*ll2^11— )3^- H 2 L,H3
H
—
-NHS(0) 2 -
VIII, IX, X
/p-iTT \ /r~<TT PT-T-P^T-TA /T^TT ^ PT-T
-(Cri 2 )2(^W2^tl— 1-/11 , 4(.^"2)4'-'ll3
"rpw ^ "
-NHS(0) 2 -
— IX > x —
-(CH2) 10CH3
PH
"pit 2 , 3 "
-NHS(0) 2 -
-(CH 2 )i2CH 3
~CH
Irlit"
-NHS(0) 2 -
tv v
— IX, X —
//-ITT \ PTT
-(CH. 2 )i4 l -Jtl3
T^T-T
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )i 6 (_.H 3
~Fif
"rcH^ 3 "
-NHS(0) 2 -
VIII, IX, X
-(CH2)isCH 3
T^rT
"rPFO ~
-lNrlo(W )2~
— IX, x —
/PTT \ — PrjVPTT *\ PTT
-( C^li 2 )7V--li— C_-ll( L^H2)5^H3
~CH
(rvf}
-NHS(0) 2 -
-(Ly 112)7^11 ~^ii(^ri2j7*-'ii3
~Cil
"(CH ) "
-NHS(0) 2 -
/prr \ /pTJT PTT— PTT"\ f{~%X \ PTT
-((_>Ho )t5(Lvll2^11— L>H ) 2 (^ll2)4*->ll3
~TH
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
/prr \ /pT-T pu-/'[J\ PTT-PTT..
-(LJti-> )6(^H2>-ii— ^/H)3^ii2>-'ii3
~ca
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII, IX, X
/ptt \ /ptt ptt— ptr /pit \ rw
-(LJtll )2(.»-ll7^11— C/H ) 4 (<^ll7 )4^rl3
~cif
-(CH 2 ) 3 -
-NHS(0) 2 -
/"PT.T \ PT-T
pri ru
((-ta 2 ; 3
-NHS(0) 2 -
TV~Y
P^TJ 2 p^TJ 3
-Oxi2^ri3
-(CH 2 ) 3 -
-NHS(0) 2 -
— ix x —
/PTT \ ptt
-(CH,) 3 -
-NHS(O),-
\mr tv v
Vlll, 1A, A
cptt v.m.
"fH Z pH
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
/PT-T , i PTT
-(. l "-il2)isdl 3
Cl/cH 3
-(^n 2 ;3
-NHS(0) 2 -
-(t^li 2 l7LJi — ^11(^112)5^113
CH 2 CH 3
_(CH 2 ) 3 .
-NHS(0) 2 -
VIII IX X
/'PT-T "V PTT — PT-TY PTT ^ PTT
-(Lyil2)7^'H — 11(^-112)7^113
"cp/cH 3
-NHS(0) 2 -
VIII, IX, X
/p 1 1 \ /ptt pt-t— ptn /PTT \ ptt
-(^li 2 )6(^ll2^'li — v^H)2(. t " Jt:l 2j4 , -' i:1 3
— "chW —
"fr!!t"
-NHS(0) 2 -
VIII, IX, X
fPTJ \ fPTT P^TT— P^TJ^ P^U P*TJ
-(^Il2)6('^ti2^rl — V^ll )3^tl2^tl3
rH 2 pn 3
-i\rx>3\vjf2-
VIII, IX, X
CHCH
{ru \
-NHS(0) 2 -
— IX ' X —
-(CH 2 )ioCH 3
"(CH )
-NHS(0)2-
— IX, X —
//^i r \ p~ it
-(V_^H2) 12^113
-(CH 2 ) 2 CH3
-(CH7) 3 -
-NHS(0) 2 -
.'PIT \ PTT
-(^112)14^113
-(CH 2 )7CH 3
— 1p!!t" —
-NHS(0)i-
TV V
VIII, IX, X
-(CH 2 )i6CH3
-(^H 2 ; 2 ^ll3
-l*-ll2)3-
-NHS(0) 2 -
VIII, IX, X
-(Cll2)l8^tl3
-(CHDO2CH3
-(CH 2 ) 3 -
-NHS(0) 2 -
— IX ' X —
/ p ^ 1 1 \ / hi / n i 1 , / '11 \ r 'i l
-(l^U 2 )7^--ll— *_.11( ^tl 2 )5^1l3
-(CH 2 ) 2 CH3
-(CH 2 )3-
-NHS(0) 2 -
-( ^_il2 ) 7V^11 — V_,irl\ V_-rl2 )7^Jtl 3
-(CH 2 ) Z CH 3
-(CH 2 )3-
-NHS(0) 2 -
Vlll' IX X
-(^H2)6(v^H2^11— )2(^-'ll2)4^-'ll3
-(CH?)2CH3
-NHS(0) 2 -
VIII IX X
-(v_Jtl2j6(^-'ll2^-'ll -^n l3^n 2 v-rl3
-( v^i^-272^- n 3
-(CH 2 )3-
-NHS(0) 2 -
VIII, IX, X
^P^TT ^ /"P^T-T PTT— PTTi ^PTT \,r~ , 'PT,
-(^ll2)2( ^-'112^11 — )4(^-'ll2M^-'ll3
^'P'l : T,^„PT-T,
-(^112)2^113
-NHS(0) 2 -
"V PIT
-(1^112) 10^113
-CH 2 OCH->CH 3
-(CH 2 )3-
-NHS(0) 2 -
1 v
/ P" 1 7 \ /^ T I
-(L-W2;i2<-±13
-CH z O CH 2 CH 3
"rPH^ 3
-NHS(0) 2 -
— ix x —
-(1^112)14^113
-CH^OCH2CH 3
-NHS(0) 2 -
VIII IX X
-(L--H2) 16^H3
-CH20CH 2 CH 3
"rPFn
-NHS(0) 2 -
VIII, IX, X
/"PTIT \ p~'TT
-(dl2)is^ii 3
-CH2OCH2CH3
"(CH)"
-NHS(0) 2 -
IX, X
-(CH 2 )7CH=CH(CH 2 ) 5 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 7 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII, IX, X
-(CH2) 6 (CH 2 CH=CH)2(CH 2 ) 4 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII, IX, X
-(CH2)s(CH ? CH=CH)3CH 2 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII, IX, X
-(CH2) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
IX, X
-(CH 2 ) I0 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
-43-
WO 2005/018555
PCT7US2004/026157
— ix x —
-(CH 2 )i2CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 14 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII, IX, X
16^-1.-1.3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
vni, ix, x
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
-(CH 2 ) 7 CH=CH(CH 2 ) S CH3
-(CH7) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
vni, ix, x
-(CH ? ) 7 CH=CH(CH 2 )7CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
vni ix x
-(CH 2 )<i(CH2CH=CH)9(CE[2)4CI-l3
-(CH 2 ) 2 OCH3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIE, IX, X
-(CH 2 )6(CH 2 CH=CH)3CH 2 CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
vni IX X
-(CH7)i(CH 2 CH=CH)4(CH 2 )4CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
-(CH 2 ) 3 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
— dHI —
-(CH 2 ) 12 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
— ix x —
-(CH 2 ) 14CH3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
-(^112)16*— n 3
^\^lA 2 _f 3 \^±± 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 3 CH3
-(CH 2 ) 3 -
-NHS(0) 2 -
-(CH 2 )7CH=CH(CH->)sCH 3
-(CH 2 ) 3 -
-NHSCO) 2 -
VIII IX X
-(CH 2 )7CH=CH(CH 2 )7CH3
-(CH 2 ) 3 CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
-(CH 7 ) 6 (CHiCH=CH) 2 (CH->) 4 CH3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
-(CH 2 )6(CH^CH=CH) 3 CH 2 CH3
-(CH 2 )3CH 3
-(CH 2 ) 3 -
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 2 (CHiCH=CH) 4 (CHi)4CH 3
-(CH 2 ) 3 CH3
-(CH 2 ) 3 -
-NHS(0) 2 -
H
-(CH 2 ) 4 -
-NHS(0) 2 -
— ix x —
-(CH 2 ) I2CH3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
— ix' x —
-(CH",) 14 CH 3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII IX X
-(CH 2 )i 6 CH 3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-fCH^,.CH,
^n 2 ;i 8 v^n. 3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII IX X
-(CH 2 )7CH=CH(CH2) 7 CH3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH2)fi{CH,CH=CH)3CH 2 CH3
II
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH,) 2 (CH 2 CH-CH) 4 (CH 2 ) 4 CH 3
H
-(CH 2 ) 4 -
-NHS(0) 2 -
IX X
-(CHi)ioCH 3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
-CII3
-(CH 2 )4-
-NHS(0) 2 -
IX, X
-(CH 2 )i 4 CH 3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 1S CH 3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
-(CH 2 )7CH=CH(CH 2 )5CH3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH2)7CH3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) G (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )6(CH2CH=CH)3CH 2 CH3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH2)2(CH 2 CH=CH)4(CH 2 )4CH3
-CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
-(CH 2 )ioCH 3
-CH2CH3
-(CH 2 ) 4 -
-NHS(0) 2 ~
IX, X
-(CH 2 ) P CH 3
-CH 2 CH 3
-(CH 2 )„-
-NHS(0) 2 -
V v -'- L - t 2-/14 v ^- L - t 3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 16 CH 3
-CH 2 CH 3
-fCH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-CH 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 7 CH=CH(CH 2 )5CH3
-CH7CH3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )7CH3
-CH2CH3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH,) 4 CH 3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH2)6(CH 2 CH=CH) 3 CH2CH3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII IX X
-(CH2) 2 (CH 2 CH=CH) 4 (CH9)4CH3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 10 CH 3
-(CH 2 ) 2 CH 3
-fCH 2 ) 4 -
-NHS(O),-
IX, X
-(CH 2 ) 12 CH3
-(CH 2 ) 2 CH 3
-fCH 2 ) 4 -
-NHS(0) 2 -
IX, X
-(CH 2 )i 4 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 16 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 18 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHS(0) 2 -
-44-
WO 2005/018555
PCT7US2004/026157
vni, ix, x
-(CH 2 )7CH— CH(CH 2 ) 7 CH 3
fr^xJC \ r^xx
-^xl 2 j 2 Uxl 3
-(CH 2 ) 4 -
vm, ix, x
cr'xx \ err
- \ ^xa 2 )2
pp^xj 2 ^ 4
-NHS(0) 2 -
VIII, IX, X
fr^xr ^ r^xx
-(CH 2 ) 4 -
VIII, IX, X
"^^xl 2i >2^JnL 3
-(CH 2 ) 4 -
— IX, x —
-(CH 2 )ioCH 3
-OjrL 2 vJ^Jn. 2 t_-Jtl 3
-(CH 2 ) 4 -
-NHS(0) 2 -
— ix, x —
-(CH 2 )i 2 CIl3
-^xx 2 vjL^xl 2 k^rl 3
"rrH^ 4 "
-NHS(0) 2 -
— IX, X —
-(CH 2 )i4CH 3
r^xx r^r^xj p^xy
-L.Jtl2Ul^Xl2C±l 3
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )i6L,il3
-l II 2' -II n II 3
(rvi \*~
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )isCH 3
-Uxl2VJi^ri2'-'ii 3
/ p-.T_ T \ 4
-(CJrI 2 ) 4 -
>JXJCJ/'0~\.
-iNrio^vJ_;2
— IX, X
-( CH 2 ) 7 CH=CH(CH 2 )5 CH 3
-Uxa 2 Ul^rl 2 L-Jtl3
-(CH 2 )4-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )7CH 3
r- ri nPTI p '1 ]
-L-li v-li;A-X 1;
-(CH 2 )4-
-NHS(0) 2 -
VIII, IX, X
-(CH2)6(CH2CH=CH) 2 (CH2)4CH 3
-CH2OCH2CH3
-(CH 2 ) 4 -
AXXXQ/'0^
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 3 CH 2 CH 3
-CH 2 OCH 2 CH3
-(CH 2 ) 4 -
AXXXCrO^
-inx1l>(_UJ 2 -
VIII, IX, X
-(CH2)2(CH 2 CH=CH)4(CH 2 )4CH3
-CH 2 OCH 2 CH 3
-(CH 2 )4-
— IX, X —
-(CH 2 ) 10CH3
-(CJbl2j 2 UC-xl 3
"^xT^ 4 "
— IX, x —
-(CH 2 )i2CH 3
-(Cxl 2 ; 2 UL-rL 3
/pinN 4
-NHS(0) 2 -
— ix^x —
-(CH 2 )i 4 CH 3
-^xi 2 ; 2 uO-ti 3
-(CH 2 ) 4 -
VIII, IX, X
-(CH 2 ) 16 CH 3
-tC±l 2 J 2 UV_/Jtl3
-(CH 2 ) 4 -
-NJrIS(0) 2 -
VIII, IX, X
-(CH 2 )i8CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHS(0) 2 _
— IX ' x —
-(CH 2 ) 7 CH=CH(CH 2 )jCH3
-(CH 2 ) 4 -
-l\ rlp^^J^ -
VIII, IX, X
-(CH 2 )7CH=CH(CH2)7CH 3
-(CH 2 ) 4 -
VIII, IX, X
-(CH 2 )fl(CH 2 CH=CH) 2 (CH 2 )4CH3
/ p^ r t n pAp^i T
~^^xl 2 J 2 UL J rl 3
-(CH 2 ) 4 -
VIII, IX, X
/ ri \ //~ixx p~ixx ^TT\ r^TT CM
-^Xl2J2'-' l -Xl3
-(CH 2 ) 4 -
-^rl 2 j2l^niCn— L.JH. J4t,'-'il2 )4^£l3
( L^Jtlo J?A-' f ^- i 1 ,
-NHS(0)2-
VI ^ I y' x
— ix^x —
~/oxj 2 \ 4 "
-NHS(0) 2 -
— IX, x —
•:(CH 2 ) 12 CH 3
-(CH 2 ) 4 -
— ix, x —
//-ITT \ no
-(CH 2 ) 14 CH 3
rr'xx ^ r^xx
-(CH 2 ) 4 -
VIII, IX, x
fr~*zi \ OXJ
-(CH 2 ) 16 CH 3
/T^XT \ P^XX
-(,Cil 2 j3^il 3
-(CH 2 ) 4 -
VIII, IX, x
-( ( ~Jrl 2 )l8 < -tU3
/p-^XX \ p-iTI
-^L_vJtl2j 3 v^rl3
",^ 2 n 4 "
-NHS(0) 2 -
— IX, X —
/prr \ p-*xx— r^xx/r^xx *\ r^xx
-(CH9 ) 7 Ctl— CM(ChL 2 ;5L,Jtl3
f r^xx \ r rx
-(CH 2 ) 4 -
-NHS(0)i-
vm, ix, x
/p'xx \ r^xx— r^xx/T^xx ^ p'xx
iT'xx "i r^xx
— i^Tj 7 ^ 4 " —
-NHS(0)9-
VIII, IX, X
zpn \ pp-»xx p^tt- pm i\ /p^xx \ r^xx
-(dl 2 )6(Oirl 2 Oli— Ull;2V^JLi2;4^^3
//-1XI \ PITT
-(CH 2 ; 4 -
-NHS(0/9-
VIII, IX, X
/pit \ pp~*xx put- PM-J\ p" 1 l_l P' 1 j
-(CH2)6(Cn 2 CH— CJl) 3 Cri 2 OIl3
/ p ^ 1 I \ f'l 1
-(CH 2 ) 4 -
-INXIO^L-' )2~
VIII, IX, X
/p^xx \ /p~«xx n 1 pma /V^xx ~\ p~*xx
-(.^xl 2 )2\^"2^W — ^W;4(Oxl 2j )4L--xl 3
^r'xj \ r>xx
-(CH 2 ) 4 -
-NHS(0)9-
— IX ' x —
-(CH 2 ) 10 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
— IX, x —
-(CH 2 ) 12 CH 3
xx
^
-(CH 2 ) 5 -
IXj_X —
-(CH 2 ) hCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 16CH3
—
-(CH 2 )5-
-XNrio^u )2~
VIII, IX, X
-(CH 2 )igCH 3
xx
-(CH 2 )5-
-NHS(0) 2 ~
— IX, X —
/r^xj *\ r^TT— oxx/r^xx r^xj
H
—
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
< f \_\ \ r \-\ —C^\:\i c*x~\ \ ( \\
-\\M.2 )-j(^tL— l^H^ri 2 ;7^Jti3
/p^xx 2 \ 5
ANJTlo^w )2~
VIII, IX, X
-(CH2)6(CH 2 CH = CH) 2 (CH 2 )4CH 3
—
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )s(CH 2 CH=CH) 3 CH 2 CH 3
xx
—
-(CH 2 ) 5 -
-iNJCia^uj 2 -
VIII, IX, X
/pit \ //-vrj p-*xx— p'xx'i //^xx ^ r^xx
— "!^ 2 \ 5 " —
-NHS(0)2-
— IX ' x —
-(CH 2 ) 10CH3
ri
T^T
-(CH2J5-
-lNrlo^wJ 2 -
— IX ' x —
-(CH 2 )i 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
— IX ' x —
-(CH 2 )i4CH 3
T^xx 2
-(CH 2 )5-
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 16CH3
-(CH 2 )5-
"^TXJCf^l^
-1NX1SIVJJ 2 -
VIII, IX, X
-(CH 2 )i 8 CH 3
CH
-(CH 2 )5-
-INJtlo^w )2~
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-CH 3
-(CH 2 ) S -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 )7CH3
-CH3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
-CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH2) 6 (CH 2 CH=CH) 3 CH 2 CH 3
-CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-fCH 2 ) 2 (GH 2 CH=CH) 4 (CH 2 ) 4 CH3
-CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-(CH 2 )i 0 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
-45-
WO 2005/018555
PCT7US2004/026157
IX, X
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
_(CH 2 )i 4 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
_(CH 2 )i6CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )i 8 CH 3
-CH 2 CH 3
-(CH 2 ) S -
-NHS(0) 2 -
IX, X
-(CH 2 )7CH=CH(CH 2 )sCH3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 7 CH=CH(CHt) 7 CH 3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII IX, X
~(CH 2 ) 6 (CH-,CH=CH)2(CH 2 )4CH3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII IX X
-(CH 2 )6(CH 2 CH=CH) 3 CH 2 CH3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH3
-CH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
-fCH^.nCFT,
xi 2 jio>^n.3
yv^lX2J2'~-- 11 3
-(CH 2 )s-
-NHS(0) 2 -
— ix x —
-(CH 2 ) 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
— ix x —
-yK^ri2) i 4 ^n.3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
\^ rl 2)l6^ LL 2
-(CH 2 ) 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII IX X
-(CH 2 )i 8 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
-(CH 2 )7CH=CH(CH2)sCH3
-fn-M-.r'H-,
-y\^n.2j2*-' 1 x3.
-(CH 2 )s-
-NHS(0) 2 -
VIII, IX, X
-(CH2)7CH=CH(CH2)7CH 3
-(CH 2 ) 2 CH3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH2)6(CH 2 CH=CH)o(CH 2 )4CH 3
^n;j 2 ^n 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) fi (CH^CH=CH) 3 CH 2 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 2 (CHiCH=CH) 4 (CH 2 ) 4 CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHSfO) 2 -
IX, X
-fCH-ilnCII-l
-CH2OCH2CH3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-CH2OCH2CH3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 16CH 3
-CH2OCH2CH3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CHi)i 8 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-(CH->) 7 CH=CH(CH 2 )5CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-('CIL)7CH=CH(CH 2 )7CH3
-CH2OCH2CH3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CII 2 ) 6 (CII 2 CII=CH)3CH2CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 2 (CH,CH=CH) 4 (CH 2 ) 4 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-(CH 2 ) ioCH,
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
_(CII 2 ) 12 CH 3
-(CH 2 bOCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
_(CH 2 ) 14 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )20CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
_(CH 2 ) 18 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-(CH 2 )7CH=CH(CH2)sCIl3
-{CH 2 ) 2 OCH3
-(CH 2 )5-
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 7 CH=CH(CH 2 ) 7 CH3
-(CHi) 2 OCH 3
~(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII IX X
-(CH 2 )6(CH2CH=CH) 3 CH 2 CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 2 (CH 2 CH=CH)4(CH2) 4 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 12 CII 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
IX, X
-(CH 2 )i 4 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 )5-
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
_(CH 2 )i S CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
-(CH 2 )7CH=CH(CH2)5CH3
-(CH7) 3 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH2) 7 CH=CH(CH 2 ) 7 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)2(CH2)4CH 3
-(CH 2 ) 3 CH 3
-(CH 2 )5-
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 6 (CH 2 CH=CH) 3 CH2CH3
-(CHO3CH3
-(CH 2 )s-
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 2 (CH2CH=CH) 4 (CH2) 4 CIl3
-(CH 2 ) 5 -
~NHS(0) 2 -
IX, X
-(CH 2 )i 0 CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 12 CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 ~
IX, X
-(CH 2 ) 14 CH 3
H
-fCH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 1S CH 3
H
-(CH 2 )20(CH 2 )2-
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 18 CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
IX, X
-(CH 2 ) 7 CH=CH(CH2)sCH 3
H
-(CH 2 ) 2 0(CH2) 2 -
-NHS(0) 2 -
-46-
WO 2005/018555
PCT7US2004/026157
VIII IX X
^£12^2^^X1212
-NHS(0) 2 -
VIII IX, X
-(CH2)6(CH 2 CH=CH) i ( CHi) 4 CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
VIII IX X
-(CH2)6(CH^CH = CH)3CH 2 CH 3
V^n 2 j2 , -'^ll2j2
-NHS(0) 2 -
VIII IX, X
-(CH 2 )2(CH 2 CH=CH)4(CH7)4CH^
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
-(CH 2 ) 10CH3
-jNrHS(0) 2 -
— ix x —
-CH3
-(CH 2 ) 2 0(CH2)2-
— ix' x —
-(\-rl2) 14^113
-\K^ri2)2'~'\ K - xl 2'2
-NHS(0) 2 -
VIII IX X
"l^H-2jT6^1l3
= CH 2
l v -'-n-2'2'-'l , -'H2l2
-NHS(0)2-
VIII IX X
~CH
-(CH 2 )20(CH 2 ) 2 -
-NHS(0) 2 -
~CH~
-(CH 2 ) 2 0(CH2)2-
-NHS(0) 2 -
VIII IX X
-(CH2) 7CH=CH(CHi) 7CH3
~CK
-(CH 2 ) 2 0(CH 2 ) 2 -
-NBS(0) 2 -
\7TTT TV V
V ill, 1A, JS.
/prr /-f-T-r fT-r— n^n ith vctt
~CH
-(CH2) 2 0(CH 2 )2-
-NHS(0) 2 -
V 111, LX-, JL
~ca
\^ jrl 2)2^ J \ K ~ jn 2)2
-NHS(0) 2 -
VI ^ I y x
~ca
-^il 2 ; 2 u^il2j 2 -
-(CH-i) 10CH3
CH CH
-(CH2)20(CH2)2-
-NHS(0)2-
ty' v
-^L,li 2 J 12^-113
ch'ch 3 —
\ y - J F 1 2)2^\ K -' rl 2)2
-NHS(0) 2 -
TY V
IX, X —
-(CH 2 ) 14CH3
"ci/cH 3
-^ri 2 j 2 i_H L.il 2 ;2-
-NHS(0) 2 -
"(CH 2 ) 16CH3
CKCH
-(CH 2 )20(CH2)2-
-NHS(0) 2 -
vin ix x
-^ri 2 J TS^l^
CHCtt
\yn-2)2^>V'-n-2)2
-NHS(0) 2 -
— ix x —
-^U>rl2j7^rl— v^ri^i^rl2^5^H3
PTJ 2 rH 3
-^n 2 ;2>-»i,<-ri2j2
-NHS(0)2-
VIII, IX, X
tcvt ^ r'T-r— cwr^H' vr v FT„
V.ttVtj 3
^il 2 )2^^il2>2
-NIIS(0)9-
("PT-T "> /TTT PT-I=PTlV('P14.,^PT-r,
-CH 2 CH 3
-^PHo^OfPH,^-
^n. 2 )2V-^v_n 2 >2
-NHS(0) 2 -
VIII IX X
-(CH2)6(CHiCH=CH)3CH2CH3
-CH2CH3
\^ L1 -2}2*-'K y ~' s - x 2/2
-NHS(0) 2 -
VIII IX X
-^v^rX2j2V^-'- n 2^ Jt: l ^XlMl^X^M^ii^
V ^ n 2/2 v - / V v ^ xl 2/2
-NHS(0) 2 -
-^v^rinj to^H3
-(CH 2 )->CH 3
^ rl 2;2'-'^Jl2)2
-NHS(0) 2 -
— ix x —
^il2 )2 y -'\ ^^2 )2
-NIIS(0) 2 -
— ix' x —
-(CH-,)-,CH 3
-NHS(0) 2 -
VIII IX X
-(^n 2 /To k - xl 3
-ffHiliCHi
\K^LL2)2*~' X1 -3
-NIIS(0) 2 -
VIII IX X
-(CH 2 )i8CH3
-(CH 2 )2CH 3
-(CH,) 2 0(CH 2 ) 2 -
-NHS(O),-
-(CH 2 )7CI I=Cri(CH 2 ) 5 CI I 3
\^LL2 '2*-'- n 3
-(CH2) 2 0(CH 2 )2-
-NHS(O),-
V ill, 1A_, A
-^^rl277^H ^'lJ-^*-'ii2j7^il3
-t, l -'i^2j2 l -'-n-3
-(CH 2 ) 2 0( CH 2 ) 2 -
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 6 (CH 2 CH=CH)2(CH?) 4 CH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
\/"TTT TY "V
V ill, 1.A, -A.
-^V^H 2 ^6V^l : l2'^H — V^Xl J 3 Oil 2 ^ii-3
-^n 2 i2<^ii3
-CPRo , (-,OCPH^ , )-.-
\ ^ n 2J2 yJ \ ^ n 2)2
-NHS(0) 2 -
VIII IX X
-(CH2)2(CH 2 CH=CH)4(CH7) 4 CH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
-(CH2) 10CH3
-CH 2 OCH 2 CH 3
-(CH9) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
ty' y
-(<wli 2 ,h2*->-n3
-CH 2 OCH 2 CH 3
-(CH?)iO(CH 2 )2-
-NHS(0) 2 -
— ix x —
-^H 2 Jl4«^ll3
-CH 2 OCH 2 CH 3
-(CH 2 )90(CH-j) 2 -
-NHS(0) 2 -
\77TT TV V
Vlll, 1A, .A
-CH20CH2CH 3
-\ ^n 2 )2^ , \\^ xx 2}2
-NHS(0) 2 -
VIII IX X
-(CH 2 )i8CH 3
-CH 2 OCH^CH 3
-(CHi) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
-(CH2)7CH=CH(CH 2 )sCH3
-CH 2 OCH 2 CH 3
-(CH 2 )20(CH 2 )->-
-NHS(0)i-
VIII IX X
-(CH2) 7 CH=CH(CH 2 ) 7 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 )oO(CH 2 )o-
-NIIS(0) 2 -
VIII IX X
-(CH 2 ) 6 (CH 2 CH=CH)2(CH->)4CH3
-CH2OCH2CH3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(O)-.-
VIII IX X
-(CH2)6(CH2CH=CH) 3 CH->CH3
-CH2OCH2CH3
V^H2^2 l - / V. v -^ rl 2/2
-NHS(0) 2 -
VIII IX X
-(CH 2 ) 2 (CH 2 CH=CH)4(CH7)4CH 3
-CH-jOCH 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
-(CH2)20CH 3
-( CH 2 )20( CH'j) 2 -
— ix x —
-^^Xl 2( / [2^-Tl3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
— ix' x —
-(CH 2 ) 14CH3
-(CH->)->OCH 3
-(CH 2 )20(CH 2 ) 2 -
-NHS(0) 2 -
VIII IX X
(CH \ (~T-T
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
\7TTT TV V
Vlll, 1A, A.
^r^Tjr \ r^T-T
\^H-2} 18^-^-3
-(CH 2 )dOCH 3
\S jn -2)2 y ~ J \>^ n -2)2
-NHS(0) 2 -
IX, X
-(CH 2 )7CH=CH(CH2)sCH 3
-(CH 2 ) 2 OCH 3
-(CH 2 )20(CH 2 )2-
-NHS(0)2-
VIII, IX, X
-(CH 2 ) 7 CH=CH{CH 2 ) 7 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
VIII, IX, X
-(CH2)s(CH 2 CH=CH)2(CH 2 ) 4 CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 3 CH 2 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHS(0) 2 -
VIII, IX, X
-(CH 2 )2(CH 2 CH=CH) 4 (CH 2 ) 4 CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHSCO) 2 -
IX, X
-(CH 2 )ioCH 3
-(CH 2 ) 3 CH 3
-(CH 2 )20(CH 2 )2-
-NHS(0) 2 -
-47-
WO 2005/018555
PCT7US2004/026157
-(CH2) 1 2 CH 3
cr'T-r ^\ nr.
-^dl2j3dl3
-(CH2)20(CH 2 )2 _
-NHS ( 0)2-
— ix x —
- ( ^Xl2 / 1 4CII3
-(CH 2 )3CH 3
-(CH 2 )20(CH 2 )2-
-NHS(0) 2 -
\77TT TV "V
VJ.11, 1A, A
-H_JH.2)l6^il3
-(L-H2j3dl3
t( 'H '\_f Ml 'H.^.
"1 dl2 .h^l '—tlo)!
-NH 8(0)2-
VIII IX X
-(CH 2 ) 3 CH 3
-(CH 2 )20(CH 2 ) 2 -
-NHS(0) 2 -
-(CH2)3CH3
-(CH2) 2 0(CH 2 ) 2 -
-NHS(0)2~
VIII IX X
-(l^li 2- ) 7 t_.ll— (_.ll^v_.rl2j7l-/Xl3
/'PT-T "\ P"*IT
-^dl 2 J 3 dl3
~ ^ ^2 )2*-* V dl2 / 2"
-NHS(0) 2 -
VIII IX X
,'P'TT \ f(" T-T PTJ- -P 1 ! TA ^P'TT \ r~*VC
~\\~^n.2}6\^^ i 2^^-~ ^tt- 721^112/4^113
-(CH->) 3 CH 3
-(CH 2 ) 2 0(CH2)2-
-MHS(0) 2 -
\PTTT TV V
Vlll, J A, A
/7~TJ \ / pt.T f ~JT r*Tl^ P'TT r^TT
-(^112)61^112^11 — dl J3L^±12^H3
/T^T-i ^ pt-i
-IA.,J 1 1 i i ;
"I. ^tll J2U^U2 J2"
VIII, IX, X
-(CH 2 ) 2 (CH 2 CH=CH) 4 (CH 2 )4CH 3
/p^T T \ PIT
-(CH 2 ; 2 U(dl 2 )2-
XTTT Q/rYv
VIII, IX, X
-(CH2)ioCH 3
—
-(CH 2 ) 3 -
-iNxli_-(lJ JlNri-
VIII, IX, X
-(CH 2 )l 2 CH 3
-(CH 2 ) 3 -
xnprr^/'o'Ms.TH"
-(CH 2 )i4CH 3
—
~
-(CH 2 ) 3 -
7\T"prr~ , /'o^ATtr
-INrlL^w JlNJtl-
\rrTT TV v
Vlll, 1A, A
-(CH2)idCH 3
-(CH 2 ) 3 -
VIII, IX, X
-(CH 2 )i8CH 3
—
— ^ —
-(CH 2 ) 3 -
XTT-T f^f(~\ XKVtl
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )sCH 3
-(CH 2 ) 3 -
XTU/~YrVVNTOr
-IN riO(^vJ JlNrl-
VIII, IX, X
-(CH2)7CH=CH(CH2)7CH3
— — —
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)2(CH9)4CH3
— — —
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH2)6(CH2CH=CH) 3 CH 2 CH 3
— — —
— — —
— i^ 2 s 3 —
VIII, IX, X
-(CH 2 )2(CH2CH=CH) 4 (CH2)4CH3
-(CH 2 )3-
-NHC(0)NH-
VIII, IX, X
-(CH 2 )ioCH3
— — —
-(CH 2 ) 3 -
x tt_t r^tr\ "\7vtcj
-IN ril \\ ) JIN 1 1-
VIII, IX, X
-(CH 2 )i2CH 3
TtT
-(CH 2 ) 3 -
-IN I Rv^V J jlN 11-
VIII, IX, X
-(CH 2 ) 14 CH 3
"7^
-(CH 2 ) 3 -
-In rl^\ KJ JIN II-
XH*' ^
, / 'i 1 \ / 1 1
-(^tl2)lsLM 3
"777
r/^tj \ 3
7\l F-I i YY YM\IT-T
-IN rxK^y \J JIN i l~
VIII, IX, X
/p-'TT \ rTT
-(CHj^sCJrlj
T^J 3
-(CH 2 ) 3 -
Kil-IY^/ r^MNlT-1
-IN J 1 \s\ yJ jlN rl-
VIII IX X
-(L.ri2)7L-Jtl— V_rl^tl2j5^±l3
777
i^ 2 \ 3 "
-IN J-IV-V ^ JIN 11-
Vlll, IX, X
-(Cli 2 )7Ut±— CJtl(CH2j7L,H3
~Fff
-(CH 2 )3-
-IN 1 , ; IN I 1 -
VIII IX X
77P
^p-tj \ 3
-NHC(0)NH-
j6l.*-^Jtl2^lT— Cli ) 3 UXl2Url3
"Fw 2
-(CH 2 ) 3 -
Nl l-U YiY^XII 1
-INJri^^LJ JINo-
VIII IX X
-(.d L XT'-- J 1— CI 1 )4(,d ' 2 j4d 1 3
rn
"/^!t 2 n 3 "
-NHC(0)NH~
PTT T
-(CH 2 ) 3 -
-INIH^LJ J1N11-
VIII IX X
"rnrH
/^tj 2 \ 3
-NHC(0)NH~
VIII, IX, X
-(CH 2 )i4CJri 3
rT J 2 pTJ 3
2 3
-(CH 2 ) 3 -
-INI tV_\L7 JXNrl-
VIII, IX, X
-(CH 2 )i6CH 3
— !x„ —
-(CH 2 ) 3 -
-iNrl^^u jiNri-
VIII, IX, X
-(CH 2 > 18 C.H.3
-(CH 2 ) 3 -
-NT 1C ( 0)NH-
VIII, IX, X
-(CH 2 ) 7 CH = CH(CH 2 )sCH 3
"fTrVy 3
-(CH 2 ) 3 -
-INJtT^^LJ JiNrl-
vin, ix, x
^\^tl2)y^t±— 1^11^^x12^7^113
'rirW
— i^„ 2 x 3 " —
-iN 1 Iv^ \J JiN J. L-
VIII, IX, X
-^tL2)6(,*-'ll2<--ll— til )2V^tLl!^^-3
" nT T 2 p-H 3
-(CH 2 ) 3 -
XTT-T <^ / YY^XTT-T
-iNllC^L/ JlNtL-
VIII, IX, X
-(CH2)s(CH2CH=CH)3CH 2 CH 3
"niiW
-(CH 2 ) 3 -
-lNriv-4 \J ) In 11 -
VIII, IX, X
-(Cl^^V^llZ^-"- - dl /4v*-'ll2/4*-'-"-3
CH CH
-(CH 2 )3-
-NHC(0)NH-
VIII, IX, X
-(CH 2 )ioCH 3
-^dl 2 ^2*-'-' : X3
-(CH 2 )3-
XTHT^rO^XTH"
-iNrlv_^^L/ JiNrl-
VIII, IX, X
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH2)l4CH 3
- i.dl2/2dl3
-(CH 2 ) 3 -
-IN JY.V_^^LJ JiNJtl-
-(CH2)i6CH 3
-Idl2^2eil3
-(CH 2 ) 3 -
XTWr^/TY^XTPT
-IN rlv-/^ \J JiN rl-
VIII IX X
,'P'TT \ P^T T
-(CH 2 ) 3 -
VIII IX X
/Y^tj \ ct-t— r , T-r/'<~'TT 1 ru
-K ,xi2_J 7 l -11 — . i 11 v ..t 1 1 (5^ . t
— i^ 2 x 3 " —
-NHC(0)NH-
VIII, IX, X
-(Lll2)7bn- dl^rl2j7dl3
-^Il2j2^-tl3
-(CH 2 ) 3 -
XTXJ C^(C\ "iXTPT
VIII, IX, X
-(CH2)6(CH 2 CH=CH)2(CH 2 )4CH 3
-{CH 2)2^113
-(CH 2 )3-
-lNrl^\LJ JlNrl-
VIII, IX, X
)6(Ln.2Ln--Lrl ) 3 L>xi2dl3
-(di 2 ;2 , -ii3
-(CH 2 ) 3 -
XTHT 1 /' n^XTOT
-lNil^\L^ JlNtl-
VIII, IX, X
-(CH 2 )2(CH2CH=CH)4(CH 2 )4CH3
-(CH2) 2 CH3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH 3
-CH-.OCH 2 CH 3
_(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )i 2 CH 3
-CH2OCH2CH3
-(CH 2 ) 3 -
-NFIC(0)NH-
VIII, IX, X
-(CH 2 ) I4 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHCfO)NH-
VIII, IX, X
-(CH 2 ) 16 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 18 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
-48-
WO 2005/018555
PCT7US2004/026157
vni ix x
-(CH 2 )7CH=CH(CH 2 )7CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )6(CH2CH=CH)2(CH2) 4 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CH 2 CH=CH)3 CH 2 CHj
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX, X
-(CH2)2(CH 2 CH=CH)4(CH 2 )4CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )l4CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-l <^Xl2j 16^13-3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )5CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
_(qtj 2 ) 7 cH=CH(CH 2 )7CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 )a(CH 2 CH=CH)2(CH2)4CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CH2CH=CH) 3 CH 2 CH 3
-(CH 2 ) 2 OCH 3
-(CH2/3-
-NHC(0)NH-
VIII IX X
-(CH 2 ) 2 OCH 3
-(CH 2 )3-
-NHC(0)NH-
VIII IX X
-(l_JHL 2 )ioL-W3
-(CH 2 ) 3 CH 3
-NHC(0)NH-
VIII IX X
-^H 2 Ji2^11 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
V 111, 1A., -A.
-(CH->) 14CH3
v> U ;J>^- 1 13
-NHC(0)NH-
-(CH 2 ) 3 CH3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII ix' X
^v-^£a 2 ^3^xi 3
\^"-V3
-NHC(0)NH-
VIII IX X
-(CHo) 7 CH=CH(CH 2 )sCH 3
-I i i_.n. 2 ^3^xi3
V v " J1 2-'3
-NHC(0)NH-
VIII IX X
-(CH 7 ) 7 CH=CH(CH 2 )7CH3
^v^ix 2 ^ 3 ^ 4 j.3
y*-' 1 - x v3
-NHC(0)NH-
\njj TV V
V 111, 1A, -A.
-(CHi) s (CH?CH=CH)^(CH 2 ")4CH3
_(CH 2 ) 3 CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 6 (CH9CH=CH) 3 CH 2 CH 3
l*-'- LA 2,/3 l -'- i -- l 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-(CHi) 2 (CH9CH=CH)4(CH 2 ) 4 CH 3
-(CH 2 ) 3 CH3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII IX X
-112/10^-^-3
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
V^ rl 2il2'-n 3
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-l^ii 2 ^i4^H3
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
V^- n -2/16^-'- i -- l -3
H
-(CII 2 ) 4 -
-NHC(0)NH-
VIII IX X
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CHn) 7 CII=CII(CH2)sCH 3
H
-(CH 2 ) 4 -
-NHC(0)NH~
VIII IX X
-(CH9) 7 CH— CH(CH 2 )7CH 3
-NHC(0)NH-
VIII IX X
-(CH 2 ) 6 (CH 2 CH=CH) -> ( CH 2 ) 4 CH 3
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CH2CH=CH) 3 CH 2 CH3
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 2 (CH 2 CH=CH) 4 (CH->) 4 CH 3
H
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-CH 3
-NHC(0,NH-
VIII IX X
-(CH 2 )i2CH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH2)i 4 CH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(.^n 2 iis^n 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )isCH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 7 ) 7 CH=CH(CH 2 )sCH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH2) 7 CH=CH(CH 2 )7CH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH2)a(CH?CH=CH) 2 (CH9) 4 CH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH2)6(CH2CH=CH) 3 CH 2 CH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )2(CH 2 CH=CH) 4 (CH?) 4 CH 3
-CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VTTT TV V
V 111, JLA-,
-(CH 2 )ioCH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH7)i 2 CH 3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
V^ xl -27 L4^-'- n -3
-CH9CH3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
V.^- n 2/16^- n -3
-CH2CH3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-^n 2 ;i 8 v^ii 3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH2)5CH 3
-CH 2 CH 3
-fCH,) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3
-CH2CH3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH) 2 fCH2) 4 CH3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) S (CH 2 CH=CH) 3 CH 2 CH 3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 2 (CH 2 CH=CH)4CCH2)4CH 3
-CH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 10 CH 3
-(CH 2 ) 2 CH 3
-CCH 2 ) 4 -
-NHC(0)NH-
-49-
WO 2005/018555
PCT7US2004/026157
VIII IX X
-(CH 2 )2CH3
-(CH 2 ) 4 -
-NHC(0)NH-
vm, ix, x
-(CH 2 )i4CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-( 1^X12 )16^11 3
-(CH 2 )2CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )isCH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-(CH 2 ) 2 CH3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )7CH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
vni ix x
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CEL) 4 CH 3
-(CH2) 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CH2CH=CH) 3 CH 2 CH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 4 ~
-NHC(0)NH-
VIII IX X
-(CH 2 )2(CH2CH=CH) 4 (Cri 2 )4CH 3
-(CH 2 ) 2 CH3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i 0 CH 3
-CH 2 OCH 2 CH 3
_(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i 2 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i 4 CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VTTT TV Y
Vlll, JLA.,
ten \ .cvt
-(^tl2) 16*^113
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
vni ix x
-^^112718^113
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH= : CH(CHi)5CH3
-CH 2 OCH 2 CH 3
_(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )7CIi = CH(CH 2 )7CH3
-CH 2 OCH 2 CH 3
_(CH 2 ) 4 -
-NHC(0)NH-
-fCH 2 )5(CH 2 CH=CH) 2 (CH->)4CH 3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-fCH 2 )6(CH 2 CH=CH) 3 CH 2 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIIl' IX X
-(CH->)2(CH7CH=CH)4(CH2) 4 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-rrH.i, n rHo
-(CH 2 ) 2 OCH3
-(CII 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-^n 2/ >i 4 <^ri3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-fCHiVXTk
^\_/H 2 n6^- n 3
^Xl 2 j 2 wv_.±±3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-ittm.oCtt,
l»-il2M8«-n-3
-(CH 2 ) 2 OCH3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )7CH=CH(CH-,')5CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX, X
-(CH 2 )7CH=CH(CH2)7CH 3
-(CH 2 ) 2 OCH 3
-(CII 2 ) 4 -
-NIIC(0)NH-
VIII, IX, X
-(CH 2 ) 6 (CH,CH=CH) 2 (CH 2 ) 4 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 4 -
-NHC('0)NH-
VIII IX X
-(CH 2 )6(CH2CH=CH)3CH 2 CH 3
-(CH 2 )-)OCH 3
-(CH 2 ) 4 -
-NHC(0)NH-
vm ix x
-(CH 2 ) 2 (CHiCH=CH) 4 (CH^) 4 CH3
-(CH-.)^OCH 3
-(CH 2 ) 4 ~
-NHC(0)NH-
VIII, IX, X
-fCT-TnimCTT.,
-(CH0 3 CH 3
-(CH 2 ) 4 -
-NHCfOjNH-
VIII IX X
frT-T,v-,CH-,
-^^Jl?J 1 2^H3
-(CH9) 3 CH 3
_(CII 2 ) 4 -
-NIIC(0)NH-
\/TTT TY Y
Vlll, .LA., -A
-(CH 2 )i 4 CH 3
-(CH 2 ) 3 CH 3
_(CH,) 4 -
-NHC(0)NH-
VTTT TY \
V 111, I.A., -A
-( ^H?.) 1 6CH3
-(CH 2 ) 3 CH 3
-(CH 2 )4-
-NHC(0)NH-
VIII, IX, X
-^xa 2 ; 18^113
-(CH,) 3 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )5CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 7 CH=CH(CH 2 )7CH 3
-(CH9) 3 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH2)s(CH 2 CH=CH) 2 (CH9) 4 CH3
-(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH2)6(CH 2 CH=CH)3CH2CH3
-(CH 2 )3CH 3
_(CH 2 ) 4 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )2(CH 2 CH=CH)4(CH2)4CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 4 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH 3
H
-(CH 2 V
-NHC(0)NH-
VIII IX X
-(CH 2 )i 2 CH 3
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )i4CH 3
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i 6 CH 3
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 7 CH=CH(CH 2 ")5CH3
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH7) 7 CH=CH{CH 2 )7CH 3
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) s (CH 2 CH=CH) 2 (CHo) 4 CH 3
H
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH9) 6 (CH 2 CH=CH) 3 CH 2 CH 3
H
_(CH 2 ) 5 -
-NHC(0)NH-
\/-TTT TY Y
-(CH 2 ) 2 (CH 2 CH=CH) 4 (CHn) 4 CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 10 CH 3
-CH3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 12 CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, rx, X
-(CH,) 14 CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 16 CH 3
-CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) I8 CH 3
-CH 3
-(CH 2 ) 3 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-CH 3
-(CH 2 ) 5 -
-NHCfO)NH-
-50-
WO 2005/018555
PCT7US2004/026157
VIII IX X
-(CH 2 ) 7CH=CH(CH 2 ) 7 CH3
-(CH 2 )5-
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) e (CH?CH=CH)2(CH 2 ) 4 CH3
-CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
\/TTT 1 V V
V 111, JLA., J\-
0x12/610x120x1 OH J3OXI2OXI3
-(CH 2 )5-
-NHC(0)1SIH-
VIII, IX, X
-(CH 2 )2(CH9CH=CH) 4 (CH,) 4 CH 3
-CH 3
_(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
12OXI3
-CH2CH3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
VOXl2^1 4 Oxa 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
J I6OXI3
CH 2 CH 3
-(CH 2 )s-
-NHC(0)NH-
VIII IX X
-(,U.H2^18 , ^ll3
chch
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH">)7CH=CH(CH2)sCH3
Cx/cH 3
-(CH 2 )5-
-NHC(0)NH-
VIII IX X
rr"Tr \ ptt— phvpt-t "\ ptt
-(^X12j 7 Oxl — Oxl^Oxl2j70xl3
CHCH
-NHC(0)NH-
VIII IX X
-(CH9)g(CHoCH=CH) 2 (CH->)4CH3
CHCH
-(CH 2 )s-
-NHC(0)NH-
VIII IX X
-(01l. 2 ifi^OxloOxl ^ J3OXI2OXI3
"chW —
-(CH 2 )5-
-NHC(0)NH-
VIII IX X
-(.ol^M^^o* 1 Oil j4( i v_rl2M < — n 3
"chW —
-NHC(0)NH-
VIII IX X
-(^xi 2 JioOX±3
-(Oxl 2 J 2 OxX3
"fCB[ 2 | 5
-NHC(0)NH-
VIII IX X
-^OXi2>l 2 OX13
-fPTT-YPTT..
loxl 2 ; 2 oxl3
fPH }
-NHC(0)NH-
VIII IX X
-^112) 140x13
-(CH2)2Cxi3
rrvi\
"\ 2 ' 5 ~
-NHC(0)NH-
VIII, IX, X
fPTT ^ PTT
-loxl 2 j20xl 3
-(CH 2 )s-
-NHC(0)NH-
/TTT ^ PPT
-^X12jlsOX13
fPTT-YPTT,
-loxl 2 ; 2 oxl3
-(CH 2 )s-
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )sCH3
lon 2 j 2 ori3
^on 2 ; s
-NHC(0)NH-
fPT-r ^pw^PT-iYPPT-VPHr.,
-^oxi 2 j70xi 0x1^0x12^70x13
-loxl2j20.n.3
-NIIC(0)N[I-
VIII IX X
-(CH 2 )6(CHoCH=CH) 2 (CH 2 )4CH 3
lOXl 2 J 2 OXl 3
-(CH 2 ) 5 -
-NHC(0)1SIH-
VIII, IX, X
-CCH2)6(CH 2 CH=CH) 3 CH2CH 3
-(CH 2 )2CH 3
V^n-VS ,
-NHC(0)NH-
-frrr.,wPHoPH=Pi c n,/PH-,i.<PH,
-^0x12121^1120x1 0x1^0x12^40x13
(,<-*l2;20Xl3
-(CH 2 )5-
-NHC(0)NH-
VIII IX X
-Coxl 2 )io*-ii3
-CH 2 OCH 2 CH3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-^il2h20Xl 3
-CH2OCH2CH3
-(CH 2 )s-
-NHC(0)NH-
VIII IX X
fpwr v ,rR,
-(.0x12^140x13
-CH^OCH,CH 3
-(CH,) 5 -
-NFIC(0)NH-
VIII IX X
Ho n 2jl60Xl3
-CH 2 OCHoCH 3
-(CH 2 )s-
-NIiC(0)NII-
VIII IX X
- lOXl 2 I18OXI3
-CH^OCH 2 CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIIT IX X
-(CIL) 7 CII=CH(CHi)5CH 3
-CH 2 OCH 2 CE[3
-(CH 2 )s-
-NHC(0)NH-
VIII IX X
-(CH9) 7 CH=CH(CHi) 7 CH3
-CH 2 0 CHi CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH,) 0 (CH 2 CH=CH) 2 (CH?)4CH3
-CH 2 0 CH 2 CH 3
-NHC(0)NH-
VIII IX X
"VOXl2^6v oxl 2 Oxl— Oil J3O1I20113
-CH7OCH2CH3
"(CE[ 2 ) 5 "
-NHC(0)NH-
VIII IX X
-(CH2)2(CH2CH=CH) 4 (CH 2 ) 4 CH3
-CH z O CH 2 CH 3
-(CH>) 5 -
-NHC(0)NH-
VIII IX X
-^0x12^100x13
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
cpw v pt-t..
-(.0XI2J12OXI3
-(CH 2 )20CH 3
-(CH 2 )5-
-NHC(0)NH-
\7TTT TV "V
Vlll, -La., -A.
-(CH2)i 4 Cx-[-
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
H0Xl 2 h60xl 3
-(CH 2 )20CH3
-(CH 2 )5-
-NHC(0)NH-
\77TT TV "V
-(CH 2 )isCH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH2)7CH=CH(CH2)5CH 3
-(CH 2 )iOCH 3
-(CH 2 )5-
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH2)7CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) S -
-NHC(0)NH-
VIII IX X
-(CH9) 6 (CH 2 CH=CH)2(CH 2 )4CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
-(CH2)6(CH2CH=CH)3CH2CH3
-(CH 2 )20CH 3
1.0X12 J5
-NHC(0)INH-
VIII IX X
-(CH2)2(CH 2 CH=CH)4(CH 2 )4CH3
-(CH 2 ) 2 OCH 3
_(CH 2 ) 5 -
-NHC(0)NH-
VIII IX X
- l 0X12^100X13
-(Cxi2) 3 CH 3
"rrrT^ 5 "
-NHC(0)NH-
VIII IX X
-(CH 2 ) 3 CH 3
-NHC(0)NH-
VIII IX X
cpt-t "» pt-t
-^0x12^140x13
-(CH->) 3 CH 3
"(CH)"
-NHC(0)NH-
VIII IX X
-(.OXl2'160Xl3
-(CH7) 3 CH 3
-(CH-,) S -
-NHC(0)NH-
WI T t TV "V
V 111, i-V, .A.
-(CH?)i8CH 3
-(CH 2 ) 3 CH3
-NHC(0)NH-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 ) 5 CH3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )7CH=CH(CH 2 )7CH3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH2) 6 (CH2CH=CH)2(CH 2 ) 4 CH3
-(CH 2 ) 3 CH 3
-CCH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)3CH 2 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH2) 2 (CH2CH=CH) 4 (CH 2 )4CH3
-(CH 2 ) 3 CH 3
-(CH 2 ) 5 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )i 0 CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHCfO)NH-
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VIII, IX, X
-(CH 2 )i2CH3
H
-(CH 2 )20(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i4CH 3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
H
-(CH 2 )20(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )5CH 3
H
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH 2 )7CH 3
H
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CH2CH=CH)2(CH 2 )4CH 3
H
-(CH 2 )20(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH 2 )fi(CH2CH=CH)3CH->CHi
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )2(CH2CH=CH)4(CH2)4CH3
H
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
V 1 — -11-2/ 10^-1^-3
-CH 3
-(CH2) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i 2 CH 3
-CH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-^^xi 2 ^i4^n 3
-CH 3
-(CH2) 2 0(CH 2 )2-
-NHC(0)NH-
\/TlT TV V
Vlll, 1A, J\
-(CH 2 ) ifiCH 3
-CH 3
VV^112^ 2 ^'V x -'l J -2y2
~NHC(0)NH-
VIII IX X
-^112)18^113
-CH 3
-(CH 2 )20(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(t^tl 2 J 7 ^JnL— L^rat^lin '5^113
-(CH7)oO(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH = =CH(CH2)7CH3
'^CK
-(CH 2 ) 2 0(CH 2 V
-NHC(0)NH-
-f CH2)fi(CH7CH=CH)2( CH 2 )4CH 3
~CB
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH2)fi(CH2CH=CH) 3 CHiCH 3
-CH 3
-(CH 2 )20(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )2(CH7CH = CH)4(CH 2 )4CH 3
^\_,ll 2 / 2 w^ll 2 /2
-NHC(0)NH-
VIII IX X
//^T-T "\ r"H
-^^ri2j lo^-'iis
-CH2CH3
\\^Ll-2)2*-'\ >^lA2/2
-NHC(0)NH-
VIII, IX, X
v*-^- n -27 n^n^
-CH2CH3
-(CH' ) )oO(ClIo)')-
-NIIC(0)NH-
VIII, IX, X
112^4^113
-CH2CH3
l v - J1 2/2'- / l'-'ll272
-NHC(0)NH-
VIII, IX, X
1^112 J 16 v -'-H-3
-CH 2 CH 3
-(CH,i 2 0(CH 2 , 2 -
-NHC(0)NH-
VIII, IX, X
-fTH-^.oCTI-,
1*-112/18 > ^'113
-CH 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )7CH=CH(CH2)5CH 3
-CH 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX, X
-(CHi) 7 CH=CH(CH 2 )7CH3
-CH2CH3
-(CII 2 )20(CII 2 ) 2 -
-NHC(0)NH-
VIII IX, X
-(CH 2 )6(CH 2 CH=CH) 2 (CH 2 )4CH 3
_CH 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH->) 6 (CH 2 CH=CH) 3 CH9CH 3
-CH 2 CH 3
-(CIl2) 2 0(CH 2 ) 2 -
-NIIC(0)NH-
VIII IX X
-(CH 2 )i(CH2CH=CH)4(CH7) 4 CH3
-CH 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 7 -
-NHC(0)NH-
VIII IX X
-(CH->) 10 CTI 3
.(CH 2 ) 2 CH 3
-(CH 2 ) 2 0(CH 7 ) 2 -
-NHC(0)IMH-
VTTT TV V
V 111, 1 A.,
-(CH 2 )pCH3
-(CH^CHi
-(CII->)20(CH 2 ) 2 -
-NIIC(0)NH-
VIII, IX, X
-(CH 2 )i4CH 3
-(CH 2 ) 2 CH 3
-(CH 2 ) 2 0(CTT 2 ) 2 -
-NHC(0)NH-
VTTT TV Y
V 111, 1A_, v\.
"(^-'H?) 1 6CH3
-(CH 2 )^CH 3
V ^ll27 2*-' V ^1 12/2
-NHC(0)NH-
VIII, IX, X
-^n 2 ;i8«^rx 3
-(CH,) 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 ) 7 CH=CH(CH2)5CH3
_(CH 2 )oCH 3
-(CH 2 ) 2 0(CH2)2-
-NHC(0)NH-
VIII IX X
-(CH 2 )7CH=CH(CH2)7CH3
-(CH 2 ) 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 7 (CH9)4CH 3
-(CH 7 ) 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CHlCH=CH) 3 CH-iCH3
-(CH 7 )?CH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII, IX, X
-(CH2) 2 (CH 2 CH=CH)4(CH2)4CH3
-(CH,) 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-CH2OCH2CH3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )i4CH 3
-CH2OCH2CH3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH 2 )i 6 CH 3
-CH^OCH^CHs
-(CH 2 )20(CH 2 )2-
-NHC(0)NH-
VIII IX X
-CH90CH 2 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
~(CH 2 ) 7 CH=CH(CH 2 j5CH 3
-CH2OCH7CH3
-(Cii 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH2)7CH=CH(CH 2 ) 7 CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH 2 )6(CHiCH=CH) 2 (CH z )4CH3
-CH 2 OCH 2 CH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH?) S (CH 2 CH=CH) 3 CH2CH3
-CH 2 OCH->CH 3
-(CH 2 )20(CH 2 )2-
-NHC(0)NH-
VIII IX X
-(CH7) 2 (CH2CH=CH) 4 (CH 2 )4CH 3
-CH^OCH 2 CH 3
-(CH 7 ) 2 0(CH 7 )9-
-NHC(0)NH-
VIII, IX, X
-(CH 2 )i 0 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 12 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH,) 14 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-fCH 2 ) 16 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 )2-
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 18 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 5 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(Q)NH-
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VIII IX X
-iVI JLL^VJ JlNil-
VIII, IX, X
-(CH 2 )6(CH 2 CH=CH)7(CH'.)4CH3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII IX X
-(CH2)6(CH2CH = CH)-CH2CHt
\ ^■Tl2/2*~'*-'ll-3
VIII, IX, X
-(CH 2 ) 2 (CH 2 CH=CH>4(CH^) 4 CH 3
-(CH 2 ) 2 OCH 3
-(CH 2 ) 2 0(CH2) 2 -
-NHC(0)NH-
VIII IX X
-(CH 2 )ioCH3
-(CH2) 3 CH 3
-(CH 2 ) 2 0(CH 2 )2-
VIII IX X
-(K^£l 2 ) l 2 l^Xl 3
-(CH2) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 ~
-NHC(0)NH-
VIII IX X
-^l.±i 2 ;i4L,j^. 3
-(L^xl2^ 3 ^-0- 3
-^xi 2 j 2 u^ri 2 ; 2 -
VIII, IX X
-( L>£l 2 7 3 *-Jri 3
-I,v_/ri2j 2 v-'v\_/jn. 2 j2"
-IN 1 1 W ) 11-
VIII, IX, X
-(CH 2 )i8CH 3
-(CH 2 ) 3 CH 3
-(CH 2 )20(CH 2 )2-
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 )jCH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 2 (CH 2 ) 4 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 ) 6 (CH 2 CH=CH) 3 CH 2 CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
VIII, IX, X
-(CH 2 )2(CH2CH=CH) 4 (CH2)4CH 3
-(CH 2 ) 3 CH 3
-(CH 2 ) 2 0(CH 2 ) 2 -
-NHC(0)NH-
Example 5
Immuniz ati ons
5 C57BL/6 mice were immunized with conjugate (1 mg ovalbumin and
200 pg IRM) in 200 pi phosphate buffered saline (PBS) either subcutaneously or
intraperitoneally. Control mice were immunized with 1 mg ovalbumin in 200 pi
PBS. For analysis of primary responses, mice were sacrificed 5-7 days after
immunization. For analysis of secondary responses, the mice were boosted 7-15
10 days after the initial immunization and sacrificed 5-7 days later. Unless
otherwise indicated, lymph nodes were harvested from mice immunized
subcutaneously for analysis and spleen cells were harvested from mice
immunized intraperitoneally for analysis.
A stock IRM solution of JV-(2-{2-[4-amino-2-(2-methoxyethyl)-liy-
15 imidazo[4,5-c]quinolin-l-yl]ethoxy}ethyl)hexadecanainide was prepared by
dissolving it in DMSO to a concentration of 10 mg/ml. Ovalbumin was
dissolved in PBS to a concentration of 50 mg/ml. Fifty pi of the stock IRM
solution was added to 150 pi of PBS and then mixed by vortexing. Fifty pi of
the ovalbumin was added to the stock IRM solution and mixed by vortexing. A
20 cloudy colloidal suspension of IRM and ovalbumin resulted.
Mice were immunized on Day 0 subcutaneously as described above with
either (a) ovalbumin alone, or (b) 50 pi of the colloidal suspension of ovalbumin
and the IRM. On Day 6, draining lymph nodes were removed, homogenized,
and stained with the H-2K b /SnNFEKL tetramer to identify ovalbumin-specific T
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cells. Figure 1 shows flow cytometry data from a control mouse immunized with
ovalbumin alone; Figures 2 and 3 show data from two different mice that were
immunized with the colloidal suspension.
Ovalbumin was obtained from Sigma Chemical Company (St. Louis,
MO). Tetramers of the MHC class I molecule H-2K b bound to the dominant
ovalbumin peptide SHNFEKL were produced as described in Kedl et al., J Exp
Med, 192:1 105-13 (2000).
Compounds of the invention were found to induce, and certain
compounds may inhibit, cytokine biosynthesis when tested using the methods
described below. The compounds of Examples 1-4 induced both interferon and
tumor necrosis factor when tested using the "Cytokine Induction in Human
Cells" assay described below.
CYTOKINE INDUCTION IN HUMAN CELLS
An in vitro human blood cell system is used to assess cytokine induction.
Activity is based on the measurement of interferon-cc and tumor necrosis factor-a
20 (IFN-a and TNF-a, respectively) secreted into culture media as described by
Testerman et. al. in "Cytokine Induction by the Immunomodulators Imiquimod
and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
Blood Cell Preparation for Culture
25 Whole blood from healthy human donors is collected by venipuncture
into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMC) are
separated from whole blood by density gradient centrifugation using
HISTOPAQUE-1077. Blood is diluted 1:1 with Dulbecco's Phosphate Buffered
Saline (DPBS) or Hank's Balanced Salts Solution (HBSS). The PBMC layer is
30 collected and washed twice with DPBS or HBSS and resuspended at 4 x 10 6
cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat
bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson
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Labwaxe, Lincoln Park, NJ) containing an equal volume of RPMI complete
media containing test compound.
Compound Preparation
5 The compounds are solubilized in dimethyl sulfoxide (DMSO). The
DMSO concentration should not exceed a final concentration of 1% for addition
to the culture wells. The compounds are generally tested at concentrations
ranging from 30-0.014 micromolar (uM).
10 Incubation
The solution of test compound is added at 60 uM to the first well
containing RPMI complete and serial 3 fold dilutions are made in the wells. The
PBMC suspension is then added to the wells in an equal volume, bringing the
test compound concentrations to the desired range (30-0.014 uM). The final
15 concentration of PBMC suspension is 2 x 10 6 cells/mL. The plates are covered
with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at
37°C in a 5% carbon dioxide atmosphere.
Separation
20 Following incubation the plates are centrifuged for 10 minutes at 1000
rpm (approximately 200 x g) at 4°C. The cell-free culture supernatant is
removed with a sterile polypropylene pipet and transferred to sterile
polypropylene tubes. Samples are maintained at -30°C to -70°C until analysis.
The samples are analyzed for IFN-a by ELISA and for TNF-a by ELISA or
25 IGEN Assay.
IFN-a and TNF-a Analysis by ELISA
IFN-a concentration is determined by ELISA using a Human Multi-
Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are
30 expressed in pg/mL.
TNF-a concentration is determined using ELISA kits available from
Biosource International, Camarillo, CA. Alternately, the TNF-a concentration
can be determined by ORIGEN M-Series Immunoassay and read on an IGEN M-
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8 analyzer from IGEN International, Gaithersburg, MD. The immunoassay uses
a human TNF-cc capture and detection antibody pair from Biosource
International, Camarillo, CA. Results are expressed in pg/mL.
5 CYTOKINE INHIBITION IN MOUSE CELLS
The mouse macrophage cell line Raw 264.7 is used to assess the ability
of compounds to inhibit tumor necrosis factor-a (TNF-a) production upon
stimulation by lipopolysaccharide (LPS).
10 Single Concentration Assay:
Blood Cell Preparation for Culture
Raw cells (ATCC) are harvested by gentle scraping and then counted.
The cell suspension is brought to 3 x 10 5 cells/mL in RPMI with 10 % fetal
bovine serum (FBS). Cell suspension (100 uL) is added to 96-well flat bottom
15 sterile tissues culture plates (Becton Dickinson Labware, Lincoln Park, NJ). The
final concentration of cells is 3 x 10 4 cells/well. The plates are incubated for 3
hours. Prior to the addition of test compound the medium is replaced with
colorless RPMI medium with 3 % FBS.
20 Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The
DMSO concentration should not exceed a final concentration of 1 % for addition
to the culture wells. Compounds are tested at 5uM. LPS (Lipopolysaccaride
from Salmonella typhimurium, Sigma- Aldrich) is diluted with colorless RPMI to
25 the EC70 concentration as measured by a dose response assay.
Incubation
A solution of test compound (lul) is added to each well. The plates are
mixed on a microtiter plate shaker for 1 minute and then placed in an incubator.
30 Twenty minutes later the solution of LPS (1 uL, EC70 concentration ~ 10 ng/ml)
is added and the plates are mixed for 1 minute on a shaker. The plates are
incubated for 18 to 24 hours at 37 °C in a 5 % carbon dioxide atmosphere.
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TNF-a Analysis
Following the incubation the supernatant is removed with a pipet. TNF-a
concentration is determined by ELISA using a mouse TNF- a kit (from
Biosource International, Camarillo, CA). Results are expressed in pg/mL. TNF-
5 a expression upon LPS stimulation alone is considered a 100% response.
Dose Response Assay:
Blood Cell Preparation for Culture
10 Raw cells (ATCC) are harvested by gentle scraping and then counted.
The cell suspension is brought to 4 x 10 5 cells/mL in RPMI with 10 % FBS. Cell
suspension (250 pL) is added to 48-well flat bottom sterile tissues culture plates
(Costar, Cambridge, MA). The final concentration of cells is 1 x 10 5 cells/well.
The plates are incubated for 3 hours. Prior to the addition of test compound the
15 medium is replaced with colorless RPMI medium with 3 % FBS.
Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The
DMSO concentration should not exceed a final concentration of 1% for addition
20 to the culture wells. Compounds are tested at 0.03, 0.1, 0.3, 1, 3, 5 and 10 uM.
LPS (Lipopolysaccaride from Salmonella typhimurium, Sigma- Aldrich) is
diluted with colorless RPMI to the EC 70 concentration as measured by dose
response assay.
25 Incubation
A solution of test compound (200 pi) is added to each well. The plates
are mixed on a microliter plate shaker for 1 minute and then placed in an
incubator. Twenty minutes later the solution of LPS (200 u,L, EC 70 concentration
approximately 10 ng/ml) is added and the plates are mixed for 1 minute on a
30 shaker. The plates are incubated for 18 to 24 hours at 37 °C in a 5 % carbon
dioxide atmosphere.
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TNF-a Analysis
Following the incubation the supernatant is removed with a pipet. TNF-a
concentration is determined by ELISA using a mouse TNF- a kit (from
Biosource International, Camarillo, CA). Results are expressed in pg/mL. TNF-
5 a expression upon LPS stimulation alone is considered a 100% response.
The complete disclosures of the patents, patent documents, and
publications cited herein are incorporated by reference in their entirety as if each
were individually incorporated. The present invention has been described with
10 reference to several embodiments thereof. The foregoing illustrative
embodiments and examples have been provided for clarity of understanding
only, and no unnecessary limitations are to be understood therefrom. It will be
apparent to those skilled in the art that many changes can be made to the
described embodiments without departing from the spirit and scope of the
1 5 invention. Thus, the scope of the invention is intended to be limited only by the
claims that follow.
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WHAT IS CLAIMED IS:
1 . A compound of the following Formula I:
■or"?
wherein:
Ri has the formula alkylene-L-Ri-i, alkenylene-L-Ri_i, or
alkynylene-L-Ri-i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups;
L is a bond or a functional linking group; and
Ri_i is a linear or branched aliphatic group having at least
1 1 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds;
R" is hydrogen or a non-interfering substituent;
R A and Rb are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
alkenyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
or when taken together, R A and R B form a fused aryl ring or heteroaryl
ring containing one heteroatom or a fused 5- to 7-membered saturated ring,
optionally containing one heteroatom, wherein the heteroatom is selected from
the group consisting of N and S, and wherein the aryl, heteroaryl, or 5- to 7-
membered saturated ring is unsubstituted or substituted by one or more non-
interfering substituents; and
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each R 3 is independently selected from the group consisting of hydrogen
and alkyl;
with the proviso that when L is -NH-S(0) 2 - and R A and R B join to form
an unsubstituted benzene ring, Rn is a linear or branched aliphatic group having
5 greater than 16 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds; and with the further proviso that when L is -NH-C(O)- and
Ra and R B join to form an unsubstituted pyridine ring, Rj.j is a linear or
branched aliphatic group having greater than 1 1 carbon atoms, optionally
including one or more unsaturated carbon-carbon bonds;
10 or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 wherein when taken together, R A and
R B form a fused 5- to 7-membered saturated ring, optionally containing one
heteroatom selected from the group consisting of N and S, and unsubstituted or
15 substituted by one or more substituents selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
20 haloalkyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 .
25 3. The compound or salt of claim 1 wherein R A and R B are each
independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
30 alkenyl,
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alkoxy,.
alkylthio and
-N(R 3 ) 2 .
5 4. The compound or salt of claim 1 wherein R A and R B form a fused aryl or
heteroaryl ring.
5. The compound or salt of claim 1 wherein R A and R B fonn a fused 5- to 7-
membered saturated ring.
10
6. The compound or salt of claim 1 wherein when taken together, R A and
R B form a fused aiyl ring or heteroaryl ring containing one heteroatom selected
from the group consisting of N and S wherein the aryl or heteroaryl ring is
unsubstituted or substituted by one or more R groups;
15 or when taken together, R A and R B form a fused 5- to 7-membered
saturated ring, optionally containing one heteroatom selected from the group
consisting of N and S, and unsubstituted or substituted by one or more R groups;
each R is independently selected from the group consisting of
halogen,
20 hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
25 alkylthio, and
-N(R 3 ) 2 -
7. The compound or salt of claim 6 wherein R A and R B form a fused
benzene ring which is unsubstituted.
30
8. The compound or salt of claim 6 wherein R A and R B form a fused
pyridine ring which is unsubstituted.
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9. The compound or salt of any one of claims 1 through 8 wherein R" is
selected from the group consisting of:
hydrogen;
alkyl;
5 alkenyl;
aryl;
heteroaryl;
heterocyclyl;
alkylene-Y-alkyl;
10 alkylene-Y- alkenyl;
alkylene-Y-aryl; and
alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of:
-OH;
15 halogen;
-N(R4) 2 ;
-CCOVCi.ioalkyl;
-C(O)-O-Ci. 10 alkyl;
-N 3 ;
20 aryl;
heteroaryl;
heterocyclyl;
-C(0)-aryl; and
-C(0)-heteroaryl;
25 wherein: Y is -G- or -S(O) 0 -2S and each R 4 is independently selected from the
group consisting of hydrogen, Ci-ioalkyl, and C 2 -ioalkenyl.
10. The compound or salt of any one of claims 1 through 9 wherein L is a
bond or a functional linking group selected from the group consisting of
30 -NH-S(0) 2 - 5 -NH-C(O)-, -NH-C(S)-, -NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -,
-NH-C(S)-NR 3 -, -NH-C(0)-0-, -O-, -S-, and -S(0) 2 -.
-62-
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1 1 . The compound or salt of claim 10 wherein L is a bond or a functional
linking group selected from the group consisting of -NH-C(O)-, -NH-S(0) 2 -, and
-NH-C(0)-N(R 3 )-.
5 12. The compound or salt of any one of claims 1 through 1 1 wherein Ri-i is a
linear or branched aliphatic group having 1 1-20 carbon atoms, optionally
including one or more unsaturated carbon-carbon bonds.
13. The compound or salt of claim 12 wherein Ri_i is a linear or branched
10 aliphatic group having 12-20 carbon atoms, optionally including one or more
unsaturated carbon-carbon bonds.
14. The compound or salt of claim 13 wherein R^ is a straight chain
Ci2-C 20 alkyl.
15
15. A compound of the following Formula EI:
NH,
20
n
wherein:
Ri has the formula alkylene-L-Ri-i, alkenylene-L-Ri-i, or
alkynylene-L-Ri_i, wherein:
25
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups;
L is a bond or a functional linking group selected from the
group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
-63-
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Ri_i is a linear or branched aliphatic group having at least
1 1 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds;
R 2 is selected from the group consisting of:
5 hydrogen;
alkyl;
alkenyl;
aryl;
heteroaryl;
10 heterocyclyl;
atkylene-Y-alkyl;
alkylene-Y- alkenyl;
alkylene-Y-aryl; and
alkyl or alkenyl substituted by one or more substituents selected
1 5 from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
-C(O)-Ci_i 0 alkyl;
20 -C(0)-0-Ci_ioaIkyl;
-N 3 ;
aryl;
heteroaryl;
heterocyclyl;
25 -C(0)-aryl; and
-C(0)-heteroaryl;
wherein: Y is -O- or -S(O) 0 -2-; and each R4 is
independently selected from the group consisting of hydrogen,
Ci.ioalkyl, and C 2 -ioalkenyl;
30 Ra and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
WO 2005/018555
PCT7US2004/026157
alkenyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
5 or when taken together, Ra and R B form a fused aryl ring or heteroaryl
ring containing one heteroatom wherein the aryl or heteroaryl ring is
unsuhstituted or substituted by one or more R groups; or when taken together, R A
and R B form a fused 5- to 7-membered saturated ring, optionally containing one
heteroatom selected from the group consisting of N and S, and misubstituted or
10 substituted by one or more R groups; wherein R is selected from the group
consisting of
halogen,
hydroxy,
alkyl,
15 alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 .
20 and
R 3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-S(0 2 )- and R A and R B join to form an
unsubstituted benzene ring, is a linear or branched aliphatic group having at
least 1 6 carbon atoms, optionally including one or more unsaturated carbon-
25 carbon bonds; and with the further proviso that when L is -NH-C(O)- and R A and
R B join to form an unsubstituted pyridine ring, Rj.i is a linear or branched
aliphatic group having greater than 1 1 carbon atoms, optionally including one or
more unsaturated carbon-carbon bonds;
or a pharmaceutically acceptable salt thereof.
30
16. The compound or salt of claim 15 wherein Ri has the formula
alkylene-L-Ri-i and the alkylene is optionally interrupted with one -O- group.
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1 7. The compound or salt of claim 16 wherein Ri has the formula
Ci-5alkylene-L-Ri-i and the Ci. 5 alkylene is optionally interrupted with one -O-
group.
1 8. The compound or salt of claim 15 wherein R 2 is selected from the group
consisting of hydrogen, alkyl, and alkylene-O-alkyl.
19. A compound of the following Formula II:
wherein:
Ri has the formula alkylene-L-Ri-i, alkenylene-L-R].i, or
alkynylene-L-Ri.i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups;
L is a bond or a functional linking group selected from the
group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
Ri_i is a linear or branched aliphatic group having at least
1 1 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds;
R 2 is selected from the group consisting of:
hydrogen;
alkyl;
alkenyl;
aryl;
heteroaryl;
NH 2
n
-66-
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heterocyclyl;
alkylene-Y-alkyl;
alkylene- Y- alkenyl;
alkylene-Y-aryl; and
5 alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
10 -C(O)-Ci. 10 alkyl;
-C^-O-d.ioalkyl;
-N 3 ;
aryl;
heteroaryl;
15 heterocyclyl;
-C(0)-aryl; and
-C(0)-heteroaryl;
wherein: Y is — O— or — S(0)o-2S and each R4 is
independently selected from the group consisting of hydrogen,
20 Ci-ioalkyl, and C 2 -ioalkenyl;
R A and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
25 alkenyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ; and
R 3 is selected from the group consisting of hydrogen and alkyl;
30 or a pharmaceutically acceptable salt thereof.
20. A compound of the following Formula DI:
-67-
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m
wherein:
Ri has the fonnula alkylene-L-Rui, alkenylene-L-Ri_i, or
alkynylene-L-Ri-i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups;
Lisa bond or a functional linking group selected from the
group consisting of -NH-S(0) 2 -, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 -, -NH-C(S)-NR 3 -,
-NH-C(0)-0, -O-, -S-, and -S(0) 2 -; and
Ri_i is a linear or branched aliphatic group having at least
1 1 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds;
R is selected from the group consisting of
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
n is 0 to 4;
R 2 is selected from the group consisting of:
hydrogen;
alkyl;
alkenyl;
aryl;
heteroaryl;
-68-
WO 2005/018555
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heterocyclyl;
alkylene- Y-alkyl ;
alkylene-Y- alkenyl;
alkylene- Y-aryl; and
5 alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of:
-OH;
halogen;
-N(R4) 2 ;
10 -CCOJ-d-ioalkyl;
-C(O)-O-C M0 alkyl;
-N 3 ;
aryl;
heteroaryl;
15 heterocyclyl;
-C(0)-aryl; and
-C(0)-heteroaryl;
Yis-O- or-S(O) 0 -2S
each R4 is independently selected from the group consisting of hydrogen,
20 Ci-ioalkyl, and C2-ioalkenyl; and
R 3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-S(0 2 )-, and n is 0, R M is a linear or
branched aliphatic group having at least 16 carbon atoms, optionally including
one or more unsaturated carbon-carbon bonds;
25 or a pharmaceutically acceptable salt thereof.
2 1 . The compound or salt of claim 20 wherein n is 0.
22. A compound selected from the group consisting of the following
30 Formulas IV, V, VI, and VII:
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^R 2
VI
vn
wherein:
Ri has the formula alkylene-L-Ri_i, alkenylene-L-Ri-i, or
alkynylene-L-Ri_i, wherein:
the alkylene, alkenylene, and alkynylene groups are
optionally interrupted with one or more -O- groups;
Lisa bond or a functional linking group selected from the
group consisting of -1SIH-S(0)2-, -NH-C(O)-, -NH-C(S)-,
-NH-S(0) 2 -NR 3 -, -NH-C(0)-NR 3 - 5 -NH-C(S)-NR 3 -,
-NH-C(0)-0-, -O-, -S-, and -S(0) 2 -; and
Ri-i is a linear or branched aliphatic group having at least
1 1 carbon atoms, optionally including one or more unsaturated
carbon-carbon bonds;
R is selected from the group consisting of
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
-N(R 3 ) 2 ;
n is 0 or 1;
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R 2 is selected from the group consisting of:
hydrogen;
alkyl;
alkenyl;
5 aryl;
heteroaryl;
heterocyclyl;
alkylene- Y-alkyl ;
alkylene- Y- alkenyl;
10 alkylene- Y-aryl; and
alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of:
-OH;
halogen;
15 -N(R4) 2 ;
-C(O)-Ci_i 0 alkyl;
-C(O)-O-Ci.i 0 alkyl;
-N 3 ;
aryl;
20 heteroaryl;
heterocyclyl;
-C(0)-aryl; and
-C(0)-heteroaryl;
Yis-O-or-S(O) 0 -2-;
25 each R 4 is independently selected from the group consisting of hydrogen,
Ci-ioalkyl, and C2-ioalkenyl; and
R 3 is selected from the group consisting of hydrogen and alkyl;
with the proviso that when L is -NH-C(O)-, and n is 0, Ri_i is a linear or
branched aliphatic group having at least 12 carbon atoms, optionally including
30 one or more unsaturated carbon-carbon bonds;
or a pharmaceutically acceptable salt thereof.
23. The compound or salt of claim 22 wherein n is 0.
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24. A pharmaceutical composition comprising a therapeutically effective
amount of a compound or salt of any one of claims 1 through 23 in combination
with a pharmaceutically acceptable carrier.
5
25. A method of inducing cytokine biosynthesis in an animal comprising
administering an effective amount of a compound or salt of any one of claims 1
through 23 to the animal.
10 26. A method of treating a viral disease in an animal comprising
administering a therapeutically effective amount of a compound or salt of any
one of claims 1 through 23 to the animal.
27. A method of treating a neoplastic disease in an animal comprising
1 5 administering a therapeutically effective amount of a compound or salt of any
one of claims 1 through 23 to the animal.
28. A method of vaccinating an animal comprising administering an effecive
amount of a compound or salt of any one of claims 1 through 23 to the animal as
20 a vaccine adjuvant.
29. A method of vaccinating an animal comprising administering an effecive
amount of N-{2- {2-[4-amino-2-(2-methoxyethyl)-li7-imidazo[4 ; ,5-c]quinolin-l-
yl]ethoxy}ethyl)hexadecanamide to the animal as a vaccine adjuvant.
25
30. A method of vaccinating an animal comprising administering an effecive
amount of A^-(2-{2-[4-amino-2-(2-methoxyethyl)-li7-imidazo[4,5-c]quinolin-l-
yl]ethoxy}ethyl)octadecanamide to the animal as a vaccine adjuvant.
30 31. A method of vaccinating an animal comprising administering an effecive
amount ofN-(2- {2-[4-amino-2-(2-methoxyethyl)- li¥-imidazo [4,5 -c] quinolin- 1 -
yl]ethoxy}ethyl)dodecanamide to the animal as a vaccine adjuvant.
-72-
WO 2005/018555 PCT7US2004/026157
32. A method of vaccinating an animal comprising administering an effecive
amount of A^(2-{2-[4-amino-2-(2-memoxyethyl)-li/-imidazo[4,5-c]quinolin-l-
yl]ethoxy}ethyl)tetradecanamide to the animal as a vaccine adjuvant.
-73-
WO 2005/018555
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1/1
10 4 |
O 10 J
4 10 2
10'
10°
.07
H-2K b /SIINFEKL tetramer
TIG- 1
H-2K b /SIINFEKL tetramer
TIG- 2
10 J
10 2
10 1
10°
I ■
"I
W
10 u
10'
10^
H-2K b /SIINFEKL tetramer
TIG. 3
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